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1
Vidula, Neelima, Christina Yau, and Hope S. Rugo. "Glutaminase (GLS) expression in primary breast cancer (BC): Correlations with clinical and tumor characteristics." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 558. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.558.
Анотація:
558 Background: Tumor cells rely on glutamine for growth. GLS is a mitochondrial enzyme that is necessary for glutamine catabolism, and is present as isoforms GLS1 and GLS2. A GLS1 inhibitor is being studied in triple-negative (TN) BC. We studied GLS1 expression in primary BC to understand associations with clinical and tumor characteristics in publically available databases. Methods: GLS1 mRNA levels were evaluated using expression data from the TCGA (n = 817) dataset, with confirmation in METABRIC (n = 1992). Associations between GLS1 levels and tumor subtype were assessed using ANOVA, followed by the post-hoc Tukey test for pairwise comparisons. Pearson correlations were used to study associations between GLS1 and selected genes. Correlations with overall survival (OS) were studied with Cox proportional hazard model. For all analyses, p < 0.05 was considered significant. Results: In TCGA, the expression of GLS1 and its isoform GLS2 were significantly inversely correlated (r = -0.32). GLS1 expression was highest in TN compared to hormone receptor (HR)+ and HER2+ BC (p < 0.001). In addition, GLS1 expression was higher in basal vs luminal A, luminal B, and HER2 enriched BC (p < 0.001). GLS1 expression was significantly inversely correlated with ER (r = -0.45), PR (r = -0.34), and AR (r = -0.34), and these inverse correlations remained significant when restricted to TNBC (ER: r = -0.25, PR: r = -0.25, AR: r = -0.30). Consistent with previous reports of MYC upregulation of GLS1, GLS1 expression was significantly positively correlated with MYC (r = 0.26). Similarly, in METABRIC, GLS1 was most highly expressed in basal and TNBC, significantly inversely correlated with the expression of GLS2, ER, PR, and AR, and positively correlated with MYC expression. In METABRIC, higher GLS1 expression was associated with better OS (HR 0.91, p = 0.005); this association remained significant in the TN subset (HR 0.83, p = 0.03). Correlations between GLS1 and genes involved in metabolism and immune activation will be presented at the meeting. Conclusions: GLS1 expression is highest in basal and TNBC, is associated with MYC expression, and may have prognostic implications. These findings support ongoing trials of GLS1 inhibition in TNBC.
2
Rojas, Livisu Pajares, and Claudia Machicado Rivero. "Abstract 883: Glutaminases expression and viral infection as potential prognostic factors in cervical, head and neck and liver cancers." Cancer Research 83, no. 7_Supplement (April 4, 2023): 883. http://dx.doi.org/10.1158/1538-7445.am2023-883.
Анотація:
Abstract Human Papilloma virus (HPV)-associated Cervical squamous cell carcinoma (CESC-HPV(+)), HPV-associated Head and Neck squamous cell carcinoma (HNSCC-HPV(+)), and Hepatitis Virus B/C (HBV/HCV)-associated Liver hepatocellular carcinoma (LIHC-HBV(+)/LIHC-HCV(+)) present metabolic changes during viral transformation to adjust energy demands of transformed cells. Glutamine is used as an important energy and carbon source by cancer cells through its degradation (glutaminolysis). This latter is regulated by Glutaminases 1 and 2 (GLS1/GLS2) that convert glutamine in glutamate. GLS1/2 expression is altered both in HNSCC and LIHC but it is undetermined in CESC. We aimed to indagate if the expression of GLS1/GLS2 genes and/or status of infection by HPV, HBV, and HCV, are associated to the overall survival (OS) in CESC, HNSCC and LIHC. The Cancer Genome Atlas (TCGA) was mined and both gene expression and copy number variation (CNV) of GLS1/GLS2 was analyzed across the CESC, HNSCC and LIHC cohorts. Changes in gene expression were determined by analyzing the Log2FC and by applying statistical analysis (Welch’s T-test or One-Way ANOVA). To learn if the genomic profile was associated with phenotype, gene status was correlated with demographic and clinical data such as age group, ethnicity, race, gender, BMI, viral subtype, histologic grade, clinical stage, and tobacco/alcohol consumption. We applyed chi-squared, one-way ANOVA, and Welch’s T-tests for those assays. Kaplan Meier (K-M) plots were obtained to figure out the association of genomic and phenotypic data with OS. Our results showed that GLS1/GLS2 had no CNVs across the analyzed cohorts. However, GLS1 was upregulated in cancerous tissues both in HNSCC and LIHC (p<0.05, Log2FC>2) whereas GLS2 was downregulated in cancerous tissues in LIHC (p<0.05, Log2FC=-2). Likewise, GLS1 was upregulated both in HNSCC-HPV(-) and LIHC-HBV/HCV(+) compared with HNSCC-HPV(+) and LIHC-HBV/HCV(-), respectively (p<0.05). Also, GLS2 was over-expressed in CESC-HPV(+) and HNSCC-HPV(+) patients, compared with CESC-HPV(-) and HNSCC-HPV(-) patients, respectively (p<0.05). In the other hand, GLS2 was under-expressed in LIHC-HBV/HCV(+) compared with LIHC-HBV/HCV(-) patients (p<0.05, Log2FC = -2.5). Finally, K-M plots showed that GLS2 expression is associated with OS in CESC patients whereas the HPV subtypes and HBV/HCV infection were associated with OS in HNSCC and LIHC patients, respectively (p<0.05). We concluded that the expression of glutaminases is abnormal in patients with CESC, HNSCC, and LIHC and it depends on the status of viral infection. Since the GLS2 expression and viral infection affects the OS in the analyzed tumors, our research provides with potential prognostic markers of CESC, HNSCC and LIHC that should be validated in future studies. Citation Format: Livisu Pajares Rojas, Claudia Machicado Rivero. Glutaminases expression and viral infection as potential prognostic factors in cervical, head and neck and liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 883.
3
Bright, Scott J., Rishab Kolachina, Mariam Ben Kacem, Mandira Manandhar, Philip Jones, Timothy A. Yap, Steven H. Lin, and Gabriel O. Sawakuchi. "Abstract B030: Modulating mitochondria metabolism to radiosensitize KEAP1 mutated non-small cell lung cancer." Cancer Research 84, no. 1_Supplement (January 9, 2024): B030. http://dx.doi.org/10.1158/1538-7445.dnarepair24-b030.
Анотація:
Abstract Glutamine is the most abundant amino acid in the body. Glutamine is metabolized by the enzyme Glutaminase-1 (GLS1), and results in the formation of glutamate. Glutamate is essential for redox homeostasis, energy production, tricarboxylic acid (TCA) cycle anaplerosis, and synthesis of amino acids, lipids and nucleotides. Genetic alterations in cancer cells like in the protein Kelch-like ECH-associated protein 1 (KEAP1), can rewire cell metabolism creating greater dependency on metabolites such as glutamine. KEAP1-mutant cells rely critically on GLS1 to maintain adequate glutamate levels, TCA cycle fueling and antioxidant production. Notably, 15-20% of non-small cell lung cancers (NSCLC) have mutations in KEAP1. Therefore, GLS1 is a promising target that should show specificity in KEAP1 mutated tumors with relatively limited effects in normal tissue in a significant patient population. GLS1 inhibitors (GLS1i) are being tested in several clinical trials as a monotherapy or in combination. One combination of relevance is radiotherapy (RT)+GLS1i. GLS1 products (lipids, nucleotides, ATP or antioxidants) are heavily implicated in RT response to neutralize radiation-induced reactive oxygen species (ROS) or to serve as substrates to repair radiation-induced DNA damage. Our preliminary data indicate that a novel GLS1 inhibitor (IACS-6274) profoundly sensitizes lung cancer cell lines including KEAP1-mutant and wild type cells exposed to RT+IACS-6274, including proton RT where we saw an increase in the relative biological effectiveness. We also observed significantly more mitochondrial ROS in RT treated groups in the presence of IACS-6274, and that the radiosensitizing effects could be rescued by resupplying cells with α-ketoglutarate, the ROS scavenger N-acetyl cysteine or the ferroptosis inhibitor, ferrostatin 1. Thus, the combination of RT+IACS-6274 may offer a unique treatment combination, that could be further optimized using proton therapy. Maximizing the efficacy of RT+IACS-6274 requires identifying the mechanisms by which GLS1 inhibition sensitizes cells exposed to RT, which are currently unclear. Our findings indicate that radiation induces permanent mitochondria dysfunction, resulting in persistent higher levels of ROS which in turn can be amplified by IACS-6274 treatment. Also, in addition to increased oxidative stress as a result of reduced antioxidants, GLS1 inhibition significantly sensitizes cells to radiation by altering TCA cycle metabolism. In summary, we have identified a patient population (KEAP1 mutated NSCLC) with poorer survival and greater levels of local recurrence that may show profound sensitivity to a novel treatment strategy that exploits tumor metabolic rewiring combined with the unique physical characteristics of RT. Citation Format: Scott J. Bright, Rishab Kolachina, Mariam Ben Kacem, Mandira Manandhar, Philip Jones, Timothy A. Yap, Steven H. Lin, Gabriel O. Sawakuchi. Modulating mitochondria metabolism to radiosensitize KEAP1 mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B030.
4
Xiao, Yangbo, Rong Huang, Shenping Cao, Dafang Zhao, Zhuangwen Mao, Chuchu Xiao, Zhehua Xu, et al. "Molecular Characterization and Dietary Regulation of Glutaminase 1 (gls1) in Triploid Crucian Carp (Carassius auratus)." Fishes 7, no. 6 (December 7, 2022): 377. http://dx.doi.org/10.3390/fishes7060377.
Анотація:
Kidney-type glutaminase, encoded by the gls1 gene, plays a critical role in glutamate production and improvement of meat flavor. In this study, a gls1 gene encoding 595 amino acids was cloned from triploid crucian carp (Carassius auratus) (TCC) and showed a high similarity with the gls1 gene found in Cyprinus carpio, Sinocyclocheilus rhinocerous and Puntigrus tetrazona. Comparing the abundance of gls1 in different tissues, we found its expression level in the brain and liver were significantly higher than that in heart, gut, kidney, spleen and muscle. gls1 expression in the brain reached the highest value. In addition, the expression levels of gls1 also appeared different in diurnal variation, with the highest expression seen at 9:00, while it was low at 3:00, 6:00, 15:00 and 24:00. Furthermore, dietary regulation of gls1 expression was investigated in our study. In each feeding trial, each diet was randomly assigned to triplicate tanks. Fish were fed one of the tested diets up to satiation twice daily. The results showed that gls1 expression increased in 32% protein group and decreased in 35–41% protein group. The results of different protein source experiments showed that the expression of gls1 gene in the mixed protein group (the control group) was significantly higher than that in the fish meal and soybean meal groups. Glutamate treatment revealed that appropriate concentrations (0.10 mg/mL in vivo and 2.00% in vitro) of glutamate remarkably improved the expression of gls1. Besides, diets supplemented with 0.80–1.60% lysine-glutamate dipeptide exhibited a down regulatory impact on gls1 expression. In conclusion, this study demonstrated that the expression of gls1 in TCC was increased by 32% protein diet, mixed protein source diet and diet with 2.00% glutamate concentration, while decreased by 0.80–1.60% lysine-glutamate dipeptide. The findings of this study provide a reference for the regulation of gls1 and have a potential application in the optimization of dietary formula in aquaculture.
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Myint, Zin W., Ramon C. Sun, Patrick J. Hensley, Andrew C. James, Peng Wang, Stephen E. Strup, Robert J. McDonald, Donglin Yan, William H. St. Clair, and Derek B. Allison. "Evaluation of Glutaminase Expression in Prostate Adenocarcinoma and Correlation with Clinicopathologic Parameters." Cancers 13, no. 9 (April 29, 2021): 2157. http://dx.doi.org/10.3390/cancers13092157.
Анотація:
High Glutaminase (GLS1) expression may have prognostic implications in colorectal and breast cancers; however, high quality data for expression in prostate cancer (PCa) are lacking. The purpose of this study is to investigate the status of GLS1 expression in PCa and correlated expression levels with clinicopathologic parameters. This study was conducted in two phases: an exploratory cohort analyzing RNA-Seq data for GLS1 from The Cancer Genome Atlas (TCGA) data portal (246 PCa samples) and a GLS1 immunohistochemical protein expression cohort utilizing a tissue microarray (TMA) (154 PCa samples; 41 benign samples) for correlation with clinicopathologic parameters. In the TCGA cohort, GLS1 mRNA expression did not show a statistically significant difference in disease-free survival (DFS) but did show a small significant difference in overall survival (OS). In the TMA cohort, there was no correlation between GLS1 expression and stage, Gleason score, DFS and OS. GLS1 expression did not significantly correlate with the clinical outcomes measured; however, GLS1 expression was higher in PCa cells compared to benign epithelium. Future studies are warranted to evaluate expression levels in greater numbers of high-grade and advanced PCa samples to investigate whether there is a rational basis for GLS1 targeted therapy in a subset of patients with prostate cancer.
6
Yang, Jianqiang, Fanghui Chen, Fan Yang, and Yong Teng. "Abstract 3061: A positive feedback loop between GLS1 and c-Myc drives tumor aggressiveness." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3061. http://dx.doi.org/10.1158/1538-7445.am2024-3061.
Анотація:
Abstract Both GLS1 and c-Myc are upregulated in head and neck squamous cell carcinoma (HNSCC) primary tumors and further increased in metastatic tumors. However, the regulation between these two molecules remains largely unknown. GLS1 is a critical enzyme that regulates glutamate, which plays an important role in cancer metabolism that supports cancer growth and survival. Our bioinformatic analysis of the TCGA HNSCC cohort revealed a strong correlation between c-Myc and GLS1 expression. We describe the importance of c-Myc in regulating GLS1 and vice versa. c-Myc protein directly binds to the promoter of the GLS1 gene and upregulates its expression at the transcriptional level. Interestingly, blocking GLS1 signaling in HNSCC cells by lentiviral shRNA knockdown or CB-839 treatment downregulates USP1, one of the best characterized human DUBs, which in turn reduces c-Myc protein stability via the ubiquitin-proteasome pathway. The GLS1-c-Myc axis thus represents a novel positive feedback loop that is critical for driving the aggressiveness of HNSCC. As the treatment of HNSCC remains a major challenge, these novel findings provide the molecular basis for combining GLS1-specific inhibitors with c-Myc-targeted therapy for the treatment of HNSCC patients. Citation Format: Jianqiang Yang, Fanghui Chen, Fan Yang, Yong Teng. A positive feedback loop between GLS1 and c-Myc drives tumor aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3061.
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Ahmed, Shanzay, Peter John, Rehan Zafar Paracha, Attya Bhatti, and Monica Guma. "Docking and Molecular Dynamics Study to Identify Novel Phytobiologics from Dracaena trifasciata against Metabolic Reprogramming in Rheumatoid Arthritis." Life 12, no. 8 (July 29, 2022): 1148. http://dx.doi.org/10.3390/life12081148.
Анотація:
Enhancement of glycolysis and glutaminolysis are the two most common modalities associated with metabolic reprogramming in rheumatoid arthritis (RA). This enhancement is concomitant to the upregulation of hexokinase 2 (HK2) and glutaminase 1 (GLS1). Hence, the current study was undertaken to identify potential phytobiological inhibitors against HK2 and GLS1, from Dracaena (Sansevieria) trifasciata, an indigenous ethnomedicinal plant found in Pakistan, using computational analysis. Phytobiologics from Dracaena trifasciata were assessed for their ability to co-inhibit HK2 and GLS1 via molecular docking and molecular dynamics simulations. The results underscored seven phytobiologics with promising binding affinities for both HK2 and GLS1. Molecular dynamics simulations further elucidated that all seven identified phytobiologics inhibited HK2 by forming stable complexes but only five amongst the seven had the potential to form stable complexes with GLS1 in real time, thereby implying the potential of co-inhibition for these five compounds. Compound 28MS exhibited an equally strong binding profile for both HK2 (−8.19 kcal/mol) and GLS1 (−8.99 kcal/mol). Furthermore, it exhibited a similar trend in stability during simulation for both targets. Our results serve as a primer for a more lucid understanding towards co-inhibition of HK2 and GLS1 using multiple computational approaches. The identified phytobiologics should undergo in-vitro and in-vivo validation to corroborate their therapeutic potential in RA.
8
Kono, Michihito, Nobuya Yoshida, Kayaho Maeda, and George C. Tsokos. "Transcriptional factor ICER promotes glutaminolysis and the generation of Th17 cells." Proceedings of the National Academy of Sciences 115, no. 10 (February 20, 2018): 2478–83. http://dx.doi.org/10.1073/pnas.1714717115.
Анотація:
Glutaminolysis is a well-known source of energy for effector T cells but its contribution to each T cell subset and the mechanisms which are responsible for the control of involved metabolic enzymes are not fully understood. We report that Th17 but not Th1, Th2, or Treg cell induction in vitro depends on glutaminolysis and the up-regulation of glutaminase 1 (Gls1), the first enzyme in the glutaminolysis pathway. Both pharmacological and siRNA-based selective inhibition of Gls1 reduced in vitro Th17 differentiation and reduced the CD3/TCR-mediated increase of the mammalian target of rapamycin complex 1 activity. Treatment of mice with a Gls1 inhibitor ameliorated experimental autoimmune encephalomyelitis. Furthermore, RAG1-deficient mice that received Gls1-shRNA–transfected 2D2 T cells had reduced experimental autoimmune encephalomyelitis scores compared with those that received control-shRNA–treated cells. Next we found that T cells deficient in inducible cAMP early repressor (ICER), a transcriptional factor known to promote Th17 differentiation, display reduced activity of oxidative phosphorylation rates in the presence of glutamine and reduced Gls1 expression, both of which could be restored by ICER overexpression. Finally, we demonstrate that ICER binds to the gls1 promoter directly and increases its activity. These findings demonstrate the importance of glutaminolysis in the generation of Th17 and the direct control of Gls1 activity by the IL-17–promoting transcription factor ICER. Pharmaceutical modulation of the glutaminolysis pathway should be considered to control Th17-mediated pathology.
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Beręsewicz-Haller, Małgorzata, Olga Krupska, Paweł Bochomulski, Danuta Dudzik, Anita Chęcińska, Wojciech Hilgier, Coral Barbas, Krzysztof Zablocki та Barbara Zablocka. "Mitochondrial Metabolism behind Region-Specific Resistance to Ischemia-Reperfusion Injury in Gerbil Hippocampus. Role of PKCβII and Phosphate-Activated Glutaminase". International Journal of Molecular Sciences 22, № 16 (7 серпня 2021): 8504. http://dx.doi.org/10.3390/ijms22168504.
Анотація:
Ischemic episodes are a leading cause of death worldwide with limited therapeutic interventions. The current study explored mitochondrial phosphate-activated glutaminase (GLS1) activity modulation by PKCβII through GC-MS untargeted metabolomics approach. Mitochondria were used to elucidate the endogenous resistance of hippocampal CA2-4 and dentate gyrus (DG) to transient ischemia and reperfusion in a model of ischemic episode in gerbils. In the present investigation, male gerbils were subjected to bilateral carotids occlusion for 5 min followed by reperfusion (IR). Gerbils were randomly divided into three groups as vehicle-treated sham control, vehicle-treated IR and PKCβII specific inhibitor peptide βIIV5-3-treated IR. Vehicle or βIIV5-3 (3 mg/kg, i.v.) were administered at the moment of reperfusion. The gerbils hippocampal tissue were isolated at various time of reperfusion and cell lysates or mitochondria were isolated from CA1 and CA2-4,DG hippocampal regions. Recombinant proteins PKCβII and GLS1 were used in in vitro phosphorylation reaction and organotypic hippocampal cultures (OHC) transiently exposed to NMDA (25 μM) to evaluate the inhibition of GLS1 on neuronal viability. PKCβII co-precipitates with GAC (GLS1 isoform) in CA2-4,DG mitochondria and phosphorylates GLS1 in vitro. Cell death was dose dependently increased when GLS1 was inhibited by BPTA while inhibition of mitochondrial pyruvate carrier (MPC) attenuated cell death in NMDA-challenged OHC. Fumarate and malate were increased after IR 1h in CA2-4,DG and this was reversed by βIIV5-3 what correlated with GLS1 activity increases and earlier showed elevation of neuronal death (Krupska et al., 2017). The present study illustrates that CA2-4,DG resistance to ischemic episode at least partially rely on glutamine and glutamate utilization in mitochondria as a source of carbon to tricarboxylic acid cycle. This phenomenon depends on modulation of GLS1 activity by PKCβII and remodeling of MPC: all these do not occur in ischemia-vulnerable CA1.
10
Myint, Zin, Patrick J. Hensley, Andrew Callaway James, Peng Wang, Stephen Strup, Donglin Yan, William H. St Clair, Robert S. DiPaola, and Derek B. Allison. "Immunohistochemical evaluation of glutaminase expression in prostate adenocarcinoma and correlation with clinicopathologic parameters." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): 251. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.251.
Анотація:
251 Background: Glutaminolysis plays a significant role in the metabolic reprogramming of cancer cell growth and proliferation. Glutaminase (GLS1), the rate-limiting enzyme of the glutamine pathway, is frequently dysregulated in cancer. High GLS1 expression is reported in colorectal and breast cancers and has been found to correlate with the tumor stage and disease progression. Furthermore, a new orally bioavailable glutaminase inhibitor (CB-839) is in early phase clinical trials in select tumors. The purpose of this study is to investigate the status of GLS1 expression in prostate cancer (PCa) and to correlate expression levels with clinicopathologic parameters. Methods: Radical prostatectomy samples from 154 patients with prostate adenocarcinoma were retrospectively reviewed and used to evaluate GLS1 expression by immunohistochemistry (IHC). The IHC expression score was calculated by multiplying the intensity of the stain by the proportion of cells staining; cases were then segmented into negative, low, or high expression groups. In addition, 41 samples of benign prostate tissue were used as a control. Associations between GLS1 levels and clinicopathologic parameters were analyzed by Pearson’s chi-squared and Log-rank tests. Results: GLS1 expression in the benign controls were negative, low, and high in 59%, 41%, 0% of cases, respectively, compared to 53%, 21.5%, 25.5%, respectively, in PCa (p < 0.003). Most PCa patients were age < 60 (55.8%), white (78.6%), stage T2 (52.9%), node negative (80.5%), Grade Group 3 (44%), and non-smokers (63.6%). There was no difference between GLS1 expression and age, race, Gleason score, stage, node status, and smoking status by univariate analysis. The median biochemical-progression free survival for negative, low, and high expression was 10, 9, and 10 years, respectively (p = 0.7). Conclusions: In our study, PCa samples were more likely to have GLS1 expression compared to benign controls. Although GLS1 expression did not appear to be a prognostic marker, our cohort was enriched for cases with localized disease and low-to-intermediate grade PCa. As a result, future studies are warranted to evaluate the expression levels in high grade and advanced PCa cases to determine a role for prognostic and or therapeutic implication to justify future preclinical studies with CB-839.
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Syarifin, Andi N. K., Sri W. A. Jusman, and Mohamad Sadikin. "Gene expression and enzyme activities of carbonic anhydrase and glutaminase in rat kidneys induced by chronic systemic hypoxia." Medical Journal of Indonesia 24, no. 3 (November 9, 2015): 139–45. http://dx.doi.org/10.13181/mji.v24i3.1190.
Анотація:
Background: Hypoxia can cause acidosis. Kidney plays an essential role in maintaining acid-base balance, which involves the activities of carbonic anhydrase (CA) and glutaminase (GLS). This study is aimed to determine the expression and activities of the CA9 and GLS1 enzymes in relation to hypoxia inducible factor-1α (HIF-1α), a transcription factor protein which is a marker of hypoxia.Methods: This study was an in vivo experimental study with coupled paralel design. used 25 male Sprague-Dawley rats weighing 150-200 g. Rats were divided into 5 groups: the control group (normoxic condition) and 4 treatment groups. The latter were kept in a hypoxic chamber (10% O2: 90% N2) for 1, 3, 5 and 7 days. All rats were euthanized after treatment, kidneys excised, tissues homogenized and investigated for gene expression of CA9, GLS1 and HIF-1α. On protein level, total enzymatic activities of CA and GLS and protein of HIF-1α were also investigated. Data were analyzed statistically using ANOVA for significance, and as its alternative, used Mann-Whitney and Kruskal-Wallis test.Results: Results showed that HIF-1α mRNA increased during hypoxia, but not HIF-1α protein. It seemed that acidosis occurs in kidney tissue, indicated by increased CA9 and GLS1 mRNA expression and specific activity of total CA and GLS1. Expression of CA9 and GLS1 mRNA both showed strong positive correlation with HIF-1α mRNA, but not with HIF-1α protein.Conclusion: It is suggested that during chronic systemic hypoxia, gene expression of CA9 and GLS1 and their enzyme activities were increased as a response to acidosis and related with the expression of HIF-1α mRNA.
12
Hage, Maha El, Justine Masson, Agnès Conjard-Duplany, Bernard Ferrier, Gabriel Baverel, and Guy Martin. "Brain Slices from Glutaminase-Deficient Mice Metabolize Less Glutamine: A Cellular Metabolomic Study with Carbon 13 NMR." Journal of Cerebral Blood Flow & Metabolism 32, no. 5 (February 29, 2012): 816–24. http://dx.doi.org/10.1038/jcbfm.2012.22.
Анотація:
In the brain, glutaminase is considered to have a key role in the provision of glutamate, a major excitatory neurotransmitter. Brain slices obtained from wild-type (control) and glutaminase-deficient (GLS1 +/–) mice were incubated without glucose and with 5 or 1 mmol/L [3-13C]glutamine as substrate. At the end of the incubation, substrate removal and product formation were measured by both enzymatic and carbon 13 nuclear magnetic resonance (13C-NMR) techniques. Slices from GLS1 +/– mice consumed less [3-13C]glutamine and accumulated less [3-13C]glutamate. They also produced less 13CO2 but accumulated amounts of 13C-aspartate and 13C-gamma-aminobutyric acid (GABA) that were similar to those found with brain slices from control mice. The newly formed glutamine observed in slices from control mice remained unchanged in slices from GLS1 +/– mice. As expected, flux through glutaminase in slices from GLS1 +/– mice was found diminished. Fluxes through all enzymes of the tricarboxylic acid cycle were also reduced in brain slices from GLS1 +/– mice except through malate dehydrogenase with 5 mmol/L [3-13C]glutamine. The latter diminutions are consistent with the decreases in the production of 13CO2 also observed in the slices from these mice. It is concluded that the genetic approach used in this study confirms the key role of glutaminase for the provision of glutamate.
13
Akar, Hamurcu, and Donmez-Altuntas. "The Effects on Proliferation of siRNA-Mediated GLS1 Inhibition in MDA-MB 231 Breast Cancer Cells." Proceedings 40, no. 1 (December 26, 2019): 25. http://dx.doi.org/10.3390/proceedings2019040025.
Анотація:
The main energy source of cancer cells is known as glucose. However, they use glutamine as a second energy source besides glucose. In this study we investigated effect of siRNA mediated inhibition of glutaminase (GLS1) enzyme in the first step of glutamine metabolism on proliferation and apoptosis which are the main features of cancer. In our study we determined the cell viability by MTS analysis and the apoptosis rate by Annexin V using triple negative MDA-MB 231 cell line belonging to aggressive subtype of breast cancer. Our study demonstrated that siRNA-mediated silencing GLS1 reduced proliferation in this cancer cell line. It has been shown that inhibition of GLS1 significantly decreased cells, but there was no change in the rate of apoptosis. The cause of this decrease may be through a different pathway other than apoptosis. In this study we have shown that GLS1 inhibition does not induce apoptosis in this cell line, contrary to the literature, and activates the death pathway through a different pathway. We believe that interrupting the glutamine energy pathway for cancer cells will be promising approach for cancer treatment and further studies are needed for this.
14
Fu, Jiayao, Yiping Pu, Baoli Wang, Hui Li, Xiujuan Yang, Lisong Xie, Huan Shi, et al. "Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren’s Syndrome." Journal of Immunology Research 2022 (February 15, 2022): 1–13. http://dx.doi.org/10.1155/2022/3210200.
Анотація:
Previous studies have shown that abnormal metabolic reprogramming in CD4+ T cells could explain the occurrence of several autoimmune disorders, including Sjogren’s syndrome (SS). However, therapeutic targets of the abnormal metabolism of CD4+ T cells remain to be explored. Here, we report that glutaminase 1 (Gls1), a pivotal factor in glutaminolysis, might be involved in the pathogenesis of SS. The expression of Gls1 was upregulated in infiltrated labial CD4+ T cells and circulating CD4+ T cells of SS patients. Inhibiting Gls1 with BPTES significantly abolished the proliferation rate, as indicated by EdU, CFSE, and Western blot analyses. Additionally, BPTES downregulated the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) values of activated CD4+ T cells from SS mice. In vivo, we injected different doses of BPTES into SS-like NOD/Ltj mice and found that 10 mg/kg BPTES significantly restored the salivary flow rate. Histological and qRT–PCR analyses showed that this concentration of BPTES attenuated lymphocytic infiltration and the numbers of PCNA-positive cells and CD4+ T cells. The proportions of IFNγ-producing cells and IL-17A-producing cells and the expression of several proinflammatory cytokines, including IFNγ and IL-17A, were also affected in the salivary glands of SS-like mice. Cytokine production in circulating serum was analyzed and showed that BPTES downregulated the effector functions of Th17 cells and Th1 cells. Collectively, these results indicate a positive relationship between Gls1 and SS development. Pharmacological inhibition of Gls1 with BPTES could normalize the effector functions of CD4+ T cells and effectively attenuate the symptoms of SS.
15
Coen, Chad, Jizhi Yan, Caner Saygin, Nicole Arellano, Mirielle Nauman, Katarzyna Zawieracz, Daniele Vanni, et al. "Glutamine Metabolism Is Altered in Myeloproliferative Neoplasms and Represents a Potential Novel Therapeutic Target." Blood 142, Supplement 1 (November 28, 2023): 6350. http://dx.doi.org/10.1182/blood-2023-189731.
Анотація:
Cancer cells exhibit metabolic reprogramming to ensure sufficient production of macromolecules used to promote cell growth and proliferation. Previous studies have shown that proliferating cancer cells rely significantly on glutamine metabolism as a source of nitrogen and carbon to facilitate nucleotide and lipid biosynthesis, respectively, and to generate metabolites and/or maintain redox homeostasis. Despite this phenomenon being well characterized in many different solid and blood cancer types, very few studies have investigated the metabolic landscape of myeloproliferative neoplasms (MPNs). Glutamine catabolism begins via the uptake of glutamine through sodium-dependent transporters such as SLC1A5, and its transport to the mitochondria where it then undergoes deamination by glutaminase (GLS1) to produce glutamate. This conversion by GLS1 is the rate limiting step in the central glutaminolysis axis, making it a preferential point of study and therapeutic targeting. Indeed, many studies have explored the glutaminolysis pathway in a variety of cancers to decipher potential targets for treatment, but these studies have been extremely limited in MPNs and the potential mechanisms with respect to MPN driver mutations (CALR, JAK2, MPL) and their differential utilization of glutamine have yet to be fully explored. One previous study demonstrated that in JAK2V617F mutant-Ba/F3 cells, GLS1 expression was significantly increased and that GLS1 inhibition served as a promising intervention to suppress colony formation in patient samples but not healthy donors. To more comprehensively decipher the role of glutamine metabolism in MPNs driven by all three driver mutations ( CALR, JAK2, and MPL), we performed RNA-sequencing analysis on peripheral blood mononuclear cells (PMBCs) from MPN patients and found that genes involved in glutamine metabolism are significantly altered across the board. In contrast to the previous study mentioned above, our data demonstrate that GLS1 is not significantly up-regulated, and that MPN PBMCs are not sensitive to GLS1 inhibition. Rather, we characterized another key enzyme in glutamine metabolism, glutamine synthetase (GS) as a molecular and metabolic dependency in MPNs. GS catalyzes the reversion of glutamate into glutamine and serves to regulate nitrogen metabolism, support nucleotide biosynthesis, and most importantly synthesize glutamine to satiate the demand caused by the cancer cells' affinity for high glutamine levels. We found that GS is significantly up-regulated at the mRNA, protein, and activity level in MPNs driven by all three driver mutations, and that genetic and pharmacological inactivation of GS abrogates MPN cell proliferation in vitro. In summary, we have demonstrated that GLS1 may not be an effective therapeutic target for MPNs, and instead characterize GS as a novel dependency and potential point of therapeutic intervention.
16
Yoshikawa, Sachiko, Manabu Nagao, Ryuji Toh, Masakazu Shinohara, Takuya Iino, Yasuhiro Irino, Makoto Nishimori, et al. "Inhibition of glutaminase 1-mediated glutaminolysis improves pathological cardiac remodeling." American Journal of Physiology-Heart and Circulatory Physiology 322, no. 5 (May 1, 2022): H749—H761. http://dx.doi.org/10.1152/ajpheart.00692.2021.
Анотація:
To our knowledge, this study is the first to demonstrate that increased GLS1 expression and subsequent activation of glutaminolysis are associated with exacerbation of cardiac hypertrophy and fibrosis. Inhibiting GLS1 antagonized the adverse cardiac remodeling in vitro and in vivo, partly due to reduction of glutamine-derived metabolites, which are necessary for cellular growth and proliferation. Increased glutamine utilization for anabolic reactions in cardiac cells may be related to the pathogenesis and development of HF.
17
Feng, Yifan, Xi Yang, Jinhai Huang, Minqian Shen, Liyang Wang, Xiuping Chen, Yuanzhi Yuan, Chunqiong Dong, Xiaoping Ma, and Fei Yuan. "Pharmacological Inhibition of Glutaminase 1 Attenuates Alkali-Induced Corneal Neovascularization by Modulating Macrophages." Oxidative Medicine and Cellular Longevity 2022 (March 19, 2022): 1–19. http://dx.doi.org/10.1155/2022/1106313.
Анотація:
Corneal neovascularization (CoNV) in response to chemical burns is a leading cause of vision impairment. Although glutamine metabolism plays a crucial role in macrophage polarization, its regulatory effect on macrophages involved in chemical burn-induced corneal injury is not known. Here, we elucidated the connection between the reprogramming of glutamine metabolism in macrophages and the development of alkali burn-induced CoNV. Glutaminase 1 (GLS1) expression was upregulated in the mouse corneas damaged with alkali burns and was primarily located in F4/80-positive macrophages. Treatment with a selective oral GLS1 inhibitor, CB-839 (telaglenastat), significantly decreased the distribution of polarized M2 macrophages in the alkali-injured corneas and suppressed the development of CoNV. In vitro studies further demonstrated that glutamine deprivation or CB-839 treatment inhibited the proliferation, adhesion, and M2 polarization of bone marrow-derived macrophages (BMDMs) from C57BL/6J mice. CB-839 treatment markedly attenuated the secretion of proangiogenic factors, including vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) from interleukin-4- (IL-4-) regulated M2 macrophages. Our findings revealed that GLS1 inhibition or glutamine deprivation prevented alkali-induced CoNV by inhibiting the infiltration and M2 polarization of macrophages. This work suggests that pharmacological GLS1 inhibition is a feasible and effective treatment strategy for chemical burn-related CoNV in humans.
18
Xu, Lingfan, Yu Yin, Yanjing Li, Xufeng Chen, Yan Chang, Hong Zhang, Juan Liu, et al. "A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer." Proceedings of the National Academy of Sciences 118, no. 13 (March 22, 2021): e2012748118. http://dx.doi.org/10.1073/pnas.2012748118.
Анотація:
Cellular metabolism in cancer is significantly altered to support the uncontrolled tumor growth. How metabolic alterations contribute to hormonal therapy resistance and disease progression in prostate cancer (PCa) remains poorly understood. Here we report a glutaminase isoform switch mechanism that mediates the initial therapeutic effect but eventual failure of hormonal therapy of PCa. Androgen deprivation therapy inhibits the expression of kidney-type glutaminase (KGA), a splicing isoform of glutaminase 1 (GLS1) up-regulated by androgen receptor (AR), to achieve therapeutic effect by suppressing glutaminolysis. Eventually the tumor cells switch to the expression of glutaminase C (GAC), an androgen-independent GLS1 isoform with more potent enzymatic activity, under the androgen-deprived condition. This switch leads to increased glutamine utilization, hyperproliferation, and aggressive behavior of tumor cells. Pharmacological inhibition or RNA interference of GAC shows better treatment effect for castration-resistant PCa than for hormone-sensitive PCa in vitro and in vivo. In summary, we have identified a metabolic function of AR action in PCa and discovered that the GLS1 isoform switch is one of the key mechanisms in therapeutic resistance and disease progression.
19
Shibuya, Aya, Neil Margulis, Romain Christiano, Tobias C. Walther, and Charles Barlowe. "The Erv41–Erv46 complex serves as a retrograde receptor to retrieve escaped ER proteins." Journal of Cell Biology 208, no. 2 (January 12, 2015): 197–209. http://dx.doi.org/10.1083/jcb.201408024.
Анотація:
Signal-dependent sorting of proteins in the early secretory pathway is required for dynamic retention of endoplasmic reticulum (ER) and Golgi components. In this study, we identify the Erv41–Erv46 complex as a new retrograde receptor for retrieval of non–HDEL-bearing ER resident proteins. In cells lacking Erv41–Erv46 function, the ER enzyme glucosidase I (Gls1) was mislocalized and degraded in the vacuole. Biochemical experiments demonstrated that the luminal domain of Gls1 bound to the Erv41–Erv46 complex in a pH-dependent manner. Moreover, in vivo disturbance of the pH gradient across membranes by bafilomycin A1 treatment caused Gls1 mislocalization. Whole cell proteomic analyses of deletion strains using stable isotope labeling by amino acids in culture identified other ER resident proteins that depended on the Erv41–Erv46 complex for efficient localization. Our results support a model in which pH-dependent receptor binding of specific cargo by the Erv41–Erv46 complex in Golgi compartments identifies escaped ER resident proteins for retrieval to the ER in coat protein complex I–formed transport carriers.
20
Xiong, Jian, Thi Thu Trang Luu, Kartik Venkatachalam, Guangwei Du, and Michael X. Zhu. "Glutamine Produces Ammonium to Tune Lysosomal pH and Regulate Lysosomal Function." Cells 12, no. 1 (December 24, 2022): 80. http://dx.doi.org/10.3390/cells12010080.
Анотація:
Glutamine is one of the most abundant amino acids in the cell. In mitochondria, glutaminases 1 and 2 (GLS1/2) hydrolyze glutamine to glutamate, which serves as the precursor of multiple metabolites. Here, we show that ammonium generated during GLS1/2-mediated glutaminolysis regulates lysosomal pH and in turn lysosomal degradation. In primary human skin fibroblasts BJ cells and mouse embryonic fibroblasts, deprivation of total amino acids for 1 h increased lysosomal degradation capacity as shown by the increased turnover of lipidated microtubule-associated proteins 1A/1B light chain 3B (LC3-II), several autophagic receptors, and endocytosed DQ-BSA. Removal of glutamine but not any other amino acids from the culture medium enhanced lysosomal degradation similarly as total amino acid starvation. The presence of glutamine in regular culture media increased lysosomal pH by >0.5 pH unit and the removal of glutamine caused lysosomal acidification. GLS1/2 knockdown, GLS1 antagonist, or ammonium scavengers reduced lysosomal pH in the presence of glutamine. The addition of glutamine or NH4Cl prevented the increase in lysosomal degradation and curtailed the extension of mTORC1 function during the early time period of amino acid starvation. Our findings suggest that glutamine tunes lysosomal pH by producing ammonium, which regulates lysosomal degradation to meet the demands of cellular activities. During the early stage of amino acid starvation, the glutamine-dependent mechanism allows more efficient use of internal reserves and endocytosed proteins to extend mTORC1 activation such that the normal anabolism is not easily interrupted by a brief disruption of the amino acid supply.
21
Abdel-Magid, Ahmed F. "Glutaminase GLS1 Inhibitors as Potential Cancer Treatment." ACS Medicinal Chemistry Letters 7, no. 3 (February 2016): 207–8. http://dx.doi.org/10.1021/acsmedchemlett.6b00016.
22
Guba, B. S., and V. V. Lyubimov. "Relationship between the effective saturation energy and the amplification diagram of GLS1 and GLS2 neodymium glasses." Soviet Journal of Quantum Electronics 20, no. 9 (September 30, 1990): 1075–78. http://dx.doi.org/10.1070/qe1990v020n09abeh007407.
23
Lee, You Won, Hun Mi Choi, Seung Yeon Oh, Eun Ji Lee, Kyoung-Ho Pyo, Jae Hwan Kim, Youngseon Byeon, et al. "Abstract LB544: Targeting adaptive metabolic program as a novel treatment approach for TKIs-failed ALK-positive NSCLCs." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB544. http://dx.doi.org/10.1158/1538-7445.am2022-lb544.
Анотація:
Abstract Introduction: Acquired resistance to ALK-tyrosine kinase inhibitors (ALK-TKIs) treatment, particularly target-off resistance, remains a clinical challenge for ALK-rearranged non-small cell lung cancer (NSCLC). To explore novel vulnerabilities of ALK TKI-resistant cancer cells, we focused on their distinct metabolic pathways for growth and survival. Experimental Design: To investigate metabolic pathways in resistance mechanisms, we generated ALK-TKIs -acquired-resistant in vitro/vivo models. We screened metabolite mechanisms using metabolite assay kit, Seahorse Extracellular Flux Analyzer, real-time PCR, western blot, RNA-seq in resistant models. Results: Through an integrated transcriptomic and metabolic assay screening approach, we identified the enhanced reliance on glutamine metabolism in target-off ALK-TKIs-resistant cells. Specifically, resistant cells were characterized by upregulation of glutaminase 1 (GLS1), a mitochondrial enzyme hydrolyzing glutamine into glutamate, simultaneously with downregulation of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this metabolic state intensively accelerates glutaminolysis and subsequent mitochondrial glutamine-derived aspartate synthesis, resulting in TKI resistance by reinforcing antioxidant capacity with increase of NADPH and glutathione. Mechanistically, GLS1 inhibition elicited a marked reduction of cell growth with increase of reactive oxygen species (ROS) in resistant cells, which was restored by supplementation of exogenous aspartate. The antitumor activity of GLS1 inhibition against resistant tumor cells was further validated in in vivo experiments, patient-derived xenograft (PDX) and EML4-ALK transgenic mice. More importantly, glutaminase inhibitor CB-839 enhanced the therapeutic efficacy of anti-PD-L1 treatment in immune checkpoint blockade (ICB)-resistant EML4-ALK transgenic mice. Conclusion: Our findings highlight a new metabolic vulnerability of ALK-TKIs resistant tumors and provide a rationale for targeting GLS1 as a potential treatment option to overcome ALK-TKIs resistance. Citation Format: You Won Lee, Hun Mi Choi, Seung Yeon Oh, Eun Ji Lee, Kyoung-Ho Pyo, Jae Hwan Kim, Youngseon Byeon, Seong Gu Heo, Sun Min Lim, Min Hee Hong, Chang Gon Kim, Hye Ryun Kim, Mi Ran Yun, Byoung Chul Cho. Targeting adaptive metabolic program as a novel treatment approach for TKIs-failed ALK-positive NSCLCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB544.
24
Jovanovic, Katarina K., Léa Fléchon, Mairead Reidy, Jihye Park, Xavier Leleu, Irene M. Ghobrial, Thierry Facon, Bruno Quesnel, and Salomon Manier. "MYC Overexpressing Multiple Myeloma Are Dependent on GLS1." Blood 134, Supplement_1 (November 13, 2019): 853. http://dx.doi.org/10.1182/blood-2019-128484.
Анотація:
Introduction. MYC alterations trigger transition from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to multiple myeloma (MM). They also represent secondary genomic events inducing tumor progression. MYC localization to the nucleus and the short life of the protein are key factors that limit its direct targeting. To overcome these issues, we sought to determine the top genomic dependencies in MYC overexpressing MM by analyzing large-scale knockdown screening, followed by functional validations. Methods. We performed in silico analyses from the Dependency Map (Achilles 2.4.3) together with CCLE (Affymetrix U133+2 expression array), CLUE (Connectivity Map) and MM patient datasets (Chng et al. 2007, Gutiérrez et al. 2010, MMRF RG Dataset), to look for gene dependencies and differentially expressed pathways in MYC OE cancer cell lines and MM patient samples. We generated an isogenic model of MYC OE in U266 MM cell line by using EF1A-C-MYC lentiviral vector, and performed RNA sequencing, a quantitative proteomic analysis by Tandem Mass Tag mass spectrometry (TMT-MS) and a drug screening with ~2000 compounds. To further investigate dependency on glutamine metabolism in MYC OE cell lines, we treated them with GLS1 inhibitor CB-839 and siRNA targeting GLS1 in several cell lines with various MYC expressions and in our isogenic model. Results. By analyzing correlations between MYC expression and gene ATARiS scores corresponding to the effect of over 9000 knockdowns in 236 cell lines, we identified specific vulnerabilities of MYC overexpressing cells for the genes involved in glutamine metabolism and cell cycle pathways. Top dependencies were observed with MYC binding protein MAX (r = -0.51, p < .001), representing an internal control as it is a co-activator of MYC, followed by GLS1 (r = -0.48, p < .001) and SLC1A1 (r = -0.42, p < .001), both involved in glutamine metabolism, together with E2F6 (r = -0.41, p < .001), involved in cell cycle. To further validate dependencies obtained from Achilles data, we generated an isogenic model of MYC OE in U266 (a low c-myc expressing MM cell line). GSEA analysis of RNA seq data showed strong enrichments of translation and cell cycle pathways, with similar results observed in CCLE and MM patient data. Quantitative proteomics analysis of U266 isogenic model showed overexpression of genes involved in glutamine transport (SLC1A5; FC = 1.28, p < .05), glucose metabolism (HK2; FC = 3.68, p < .001) and cell cycle progression (CDK6; FC = 2.85, p < .001). To explore the therapeutic potential of these dependencies, we performed a primary screen of 1902 small-molecules and identified 47 compounds with potent activity on U266/MYC model. Validation screen of these hits identified three leading compounds to which U266/MYC cells showed highest sensitivity at 10 µM concentration - Torin-2 (U266/C 40.28 ± 6.74% vs. U266/MYC 16.05 ± 3.21%), LY2835219 (U266/C 52.70 ± 9.63% vs. U266/MYC 5.52 ± 0.89%) and AT7519 (U266/C 43.03 ± 4.02% vs. U266/MYC 30.13 ± 4.90%), targeting proteins involved in translation and cell cycle pathways. For the functional validation of GLS1 dependency in MYC overexpressing cells, MYC OE cell lines were treated with GLS1 inhibitors CB-839 and 968. MYC high MM cell lines showed higher sensitivity to CB-839 inhibitor compared to MYC low cell lines at 1 µM concentration, after 48 (KMS-12-BM 14.19 ± 0.07%, KMS-18 31.56 ± 2.84%, MM.1S 23.21 ± 1.21% vs. NCI-H1650 46.49 ± 3.48%, U266 52.72 ± 4.99%, LOUCY 37.14 ± 1.14%, OVCAR-3 64.14 ± 5.19%) and 72 h (KMS-18 19.69 ± 3.15%, MM.1S 15.09 ± 1.28% vs. NCI-H1650 34.82 ± 0.95%, U266 61.73 ± 1.70%, LOUCY 46.27 ± 6.27%, OVCAR-3 65.34 ± 1.23%). This suggests that GLS1 dependency in MYC OE cells offers a therapeutic window for the use of GLS1 inhibitors in MM. Conclusion. By using a combination of different datasets and models, we characterized the main dependencies in MYC overexpressing MM. Glutamine metabolism and cell cycle emerged as strong dependencies by using therapeutic inhibitors. Altogether, our results demonstrate that MYC OE MM cells are dependent on glutamine metabolism and cell cycle, and these findings can potentially lead to development of new therapeutic approaches in MM patients. Disclosures Leleu: Oncopeptide: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Manier:Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding.
25
Rojo-Báez, Indira, Raymundo S. García-Estrada, Josefina León-Félix, J. Adriana Sañudo-Barajas, and Raúl Allende-Molar. "EXPRESIÓN GÉNICA DURANTE EL PROCESO DE INFECCIÓN DE Colletotrichum truncatum (SCHWEIN.) EN PAPAYA MARADOL." Revista Fitotecnia Mexicana 44, no. 2 (June 28, 2021): 221. http://dx.doi.org/10.35196/rfm.2021.2.221.
Анотація:
Colletotrichum truncatum (Schwein.) es uno de los hongos patógenos causantes de antracnosis en papaya (Carica papaya L.). El objetivo de este estudio fue determinar los cambios en la expresión de genes relacionados con la patogenicidad de C. truncatum en su interacción con hojas de papaya Maradol. Las esporas del hongo se inocularon en hojas escindidas; se analizaron muestras de tejidos inoculados al inicio (0 h) y a las 2, 6, 16, 20, 24, 48, 60, 72, 96 y 120 h después de inoculación (hdi). Se determinó la expresión relativa de los genes quitina sintasa (CHS1), β-1-3 glucano sintasa (GLS1) y cutinasa (CUT1) respecto al tiempo. El gen CHS1 se expresó de manera permanente y alcanzó su máximo nivel de expresión a partir de las 2 hdi; el perfil de expresión del gen GLS1 coincidió con el de CHS1 al inicio de la infección, pero al final de la misma (120 hdi) la expresión de GLS1 volvió a aumentar significativamente. La expresión del gen CUT1 se consideró tardía porque el máximo se alcanzó a las 120 hdi. Estos genes se relacionan con la producción de estructuras de infección y desarrollo del patógeno en hojas de papaya Maradol durante la infección. Los resultado sugieren que la síntesis de quitina y β-1-3 glucanos se asocia con la etapa de producción de estructuras de infección (apresorios, hifas de infección, conidios y acérvulos) y que la función de la cutinasa es posterior, posiblemente durante la lisis de la cutícula del hospedante.
26
Sponagel, Jasmin, Shanshan Zhang, Prakash Chinnaiyan, Joshua Rubin, and Joseph Ippolito. "TBIO-01. SEX DIFFERENCES IN REDOX STATE UNDERLIE GLUTAMINE DEPENDENCY IN MALE GLIOBLASTOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii467. http://dx.doi.org/10.1093/neuonc/noaa222.830.
Анотація:
Abstract Glioblastoma (GBM) is an aggressive brain tumor in children and adults. It occurs more commonly in males, but female patients survive significantly longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we found that male and female GBM patient samples differ in their metabolite abundance and that males exhibit a significantly higher abundance of amino acid metabolites. We confirmed those findings in a murine model of GBM, which has previously yielded important insights into sexual dimorphism in GBM. Furthermore, we found that male GBM cell cultures are significantly more sensitive to amino acid deprivation, which was almost entirely driven by amino acids involved in the synthesis of the antioxidant glutathione. Glutaminase 1 (GLS1) mediates the conversion from glutamine to glutamate, a crucial component of glutathione. We found that male GBM cells exhibited higher levels of GLS1, suggesting they are more dependent on glutamate. Indeed, we found that male GBM cells are more sensitive to pharmacological GLS1 inhibition with the clinical inhibitor CB-839. This correlated with significantly increased reactive oxygen species (ROS) in males compared to females. We further confirmed sex differences in redox state through pharmacological depletion of glutathione that resulted in a significant increase in ROS and cell death in male GBM. Together, these data indicate that male GBM cells are more dependent on glutamine to regulate ROS levels. This reveals novel sex-specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.
27
Liu, Haixin, Haolun Tian, Pengcheng Hao, Huimin Du, Kun Wang, Yudong Qiu, Xiangrui Yin, et al. "PoRVA G9P[23] and G5P[7] infections differentially promote PEDV replication by reprogramming glutamine metabolism." PLOS Pathogens 20, no. 6 (June 21, 2024): e1012305. http://dx.doi.org/10.1371/journal.ppat.1012305.
Анотація:
PoRVA and PEDV coinfections are extremely common in clinical practice. Although coinfections of PoRVA and PEDV are known to result in increased mortality, the underlying mechanism remains unknown. Here, we found that PoRVA infection promoted PEDV infection in vivo and in vitro and that PoRVA G9P[23] (RVA-HNNY strain) enhanced PEDV replication more significantly than did PoRVA G5P[7] (RVA-SXXA strain). Metabolomic analysis revealed that RVA-HNNY more efficiently induced an increase in the intracellular glutamine content in porcine small intestinal epithelial cells than did RVA-SXXA, which more markedly promoted ATP production to facilitate PEDV replication, whereas glutamine deprivation abrogated the effect of PoRVA infection on promoting PEDV replication. Further studies showed that PoRVA infection promoted glutamine uptake by upregulating the expression of the glutamine transporter protein SLC1A5. In SLC1A5 knockout cells, PoRVA infection neither elevated intracellular glutamine nor promoted PEDV replication. During PoRVA infection, the activity and protein expression levels of glutamine catabolism-related enzymes (GLS1 and GLUD1) were also significantly increased promoting ATP production through glutamine anaplerosis into the TCA cycle. Consistent with that, siRNAs or inhibitors of GLS1 and GLUD1 significantly inhibited the promotion of PEDV replication by PoRVA. Notably, RVA-HNNY infection more markedly promoted SLC1A5, GLS1 and GLUD1 expression to more significantly increase the uptake and catabolism of glutamine than RVA-SXXA infection. Collectively, our findings illuminate a novel mechanism by which PoRVA infection promotes PEDV infection and reveal that the modulation of glutamine uptake is key for the different efficiencies of PoRVA G9P[23] and PoRVA G5P[7] in promoting PEDV replication.
28
Kim, Sewha, Do Hee Kim, Woo-Hee Jung, and Ja Seung Koo. "Expression of glutamine metabolism-related proteins according to molecular subtype of breast cancer." Endocrine-Related Cancer 20, no. 3 (March 18, 2013): 339–48. http://dx.doi.org/10.1530/erc-12-0398.
Анотація:
The aim of this study was to investigate the expression of glutamine metabolism-related proteins to determine whether glutamine is metabolized differently according to breast cancer molecular subtype. We generated a tissue microarray of 702 breast cancer patients and performed immunohistochemical staining for glutamine metabolism-related proteins, including glutaminase 1 (GLS1 (GLS)), glutamate dehydrogenase (GDH (H6PD)), and amino acid transporter-2 (ASCT2 (SLC1A5)), which were separately evaluated in tumor and stroma compartments and then analyzed by breast cancer molecular subtypes. Breast cancers were classified as follows: 293 luminal A (41.7%), 166 luminal B (23.6%), 67 HER2 type (9.6%), and 176 TNBC (25.1%). HER2 type showed the highest stromal GLS1 (P=0.001), tumoral GDH (P=0.001), stromal GDH (P<0.001), and tumoral ASCT (P<0.001) expression. We identified differential expression of glutamine metabolism-related proteins according to molecular subtype of breast cancer. The highest glutamine metabolic activity was seen in HER2-type breast cancer.
29
Sponagel, Jasmin, Shanshan Zhang, Cheryl Frankfater, Jill Jones, Din Selmanovic, Prakash Chinnaiyan, Joshua B. Rubin, and Joseph E. Ippolito. "FSMP-19. SEX DIFFERENCES IN REDOX REGULATION UNDERLIE GLUTAMINE DEPENDENCY IN MALE GLIOBLASTOMA." Neuro-Oncology Advances 3, Supplement_1 (March 1, 2021): i19—i20. http://dx.doi.org/10.1093/noajnl/vdab024.082.
Анотація:
Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. GBM occurs more commonly in males but female patients survive significantly longer. Understanding the molecular mechanisms underlying this clinical sex disparity could support novel treatment strategies to improve outcomes for GBM patients. In this regard, we found that male and female GBM patient tissues differ in their metabolite profiles and that male GBM exhibit a higher abundance of amino acid metabolites. We confirmed these findings in a murine model of GBM. Furthermore, we found that male GBM cells are more sensitive to amino acid deprivation. This male-specific dependency on amino acids is almost entirely driven by amino acids involved in reactive oxygen species (ROS) regulation and glutathione synthesis. We found that male GBM cells are more sensitive to depletion of glutathione, which resulted in a significant increase in ROS and cell death in male GBM cells. Moreover, assays of glutathione oxidation demonstrated that male GBM cells exist in a chronically oxidized state. GLS1 mediates the conversion from glutamine to glutamate, a crucial component of glutathione. We found that male GBM cells are more sensitive to GLS1 inhibition with the clinical inhibitor CB-839. This correlated with significantly increased ROS and glutathione levels as well as significantly decreased TCA cycle metabolites in male GBM. Lastly, we found that the TCA cycle metabolite α-ketoglutarate rescues the effects of CB-839 in male GBM cells. Together, these data suggest that (1) male and female GBM differ in their amino acid requirements, (2) male GBM are more dependent on glutathione to regulate ROS levels, and (3) male GBM increase glutathione synthesis at the expense of TCA cycle metabolites upon GLS1 inhibition, suggesting an increased susceptibility to drugs targeting the glutamate/glutathione axis in male GBM. Our data underline the importance of considering sex in metabolic targeting approaches.
30
Chattopadhyaya, Sikta, Raghu Nagalingam, Pavit Narhan, and Michael Czubryt. "Regulation of GLS1 Expression by Scleraxis in Cardiac Fibroblasts." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.05913.
31
Xia, Xichun, Guangchao Cao, Guodong Sun, Leqing Zhu, Yixia Tian, Yueqi Song, Chengbin Guo, et al. "GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis." Journal of Clinical Investigation 130, no. 10 (August 24, 2020): 5180–96. http://dx.doi.org/10.1172/jci129269.
32
Chen, Weihua, Weifeng Wang, Jun Zhang, Guoqiang Liao, Jie Bai, Bo Yang, Mingyue Tan, and Hua Gong. "Qici Sanling Decoction Suppresses Glutamine Consumption and Bladder Cancer Cell Growth through Inhibiting c-Myc Expression." Journal of Oncology 2022 (January 11, 2022): 1–9. http://dx.doi.org/10.1155/2022/7985468.
Анотація:
Traditional Chinese medicine (TCM) is widely used as an alternative therapy for cancer treatment in China. Glutamine catabolism plays an important role in cancer development. Qici Sanling decoction (QCSL) suppresses bladder cancer growth. However, the association between QCSL and glutamine catabolism remains unknown. In this study, different doses of QCSL were applied to T24 cells, followed by the measurements of cell viability and apoptosis using CCK-8 and Annexin V/PI assay, respectively. Furthermore, glutamine consumption was detected using the glutamine assay kit. QCSL was observed to inhibit cell growth and induced cell apoptosis in a dose-dependent manner. Analysis of glutamine consumption revealed that QCSL suppressed glutamine consumption in T24 cells. Furthermore, QCSL decreased the mRNA and protein levels of c-Myc, GLS1, and SLC1A5. All these effects induced by QCSL could be alleviated by c-Myc overexpression, indicating c-Myc was involved in the protective role of QCSL in bladder cancer. In addition, QCSL was found to inhibit tumor growth in the xenograft tumor model. The similar results were obtained in tumor samples that protein levels of c-Myc, GLS1, and SLC1A5 were decreased upon treatment with QCSL. In conclusion, QCSL suppresses glutamine consumption and bladder cancer cell growth through inhibiting c-Myc expression.
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Krishna, Gayathri, Vinod Soman Pillai, and Mohanan Valiya Veettil. "Upregulation of GLS1 Isoforms KGA and GAC Facilitates Mitochondrial Metabolism and Cell Proliferation in Epstein–Barr Virus Infected Cells." Viruses 12, no. 8 (July 27, 2020): 811. http://dx.doi.org/10.3390/v12080811.
Анотація:
Epstein–Barr virus or human herpesvirus 4 (EBV/HHV-4) is a ubiquitous human virus associated with a wide range of malignant neoplasms. The interaction between EBV latent proteins and host cellular molecules often leads to oncogenic transformation, promoting the development of EBV-associated cancers. The present study identifies a functional role of GLS1 isoforms KGA and GAC in regulating mitochondrial energy metabolism to promote EBV-infected cell proliferation. Our data demonstrate increased expression of GLS1 isoforms KGA and GAC with mitochondrial localization in latently EBV-infected cells and de novo EBV-infected PBMCs. c-Myc upregulates KGA and GAC protein levels, which in turn elevate the levels of intracellular glutamate. Further analysis demonstrated upregulated expression of mitochondrial GLUD1 and GLUD2, with a subsequent increase in alpha-ketoglutarate levels that may mark the activation of glutaminolysis. Cell proliferation and viability of latently EBV-infected cells were notably inhibited by KGA/GAC, as well as GLUD1 inhibitors. Taken together, our results suggest that c-Myc-dependent regulation of KGA and GAC enhances mitochondrial functions to support the rapid proliferation of the EBV-infected cells, and these metabolic processes could be therapeutically exploited by targeting KGA/GAC and GLUD1 to prevent EBV-associated cancers.
34
Naka, I., J. Saegusa, K. Uto, Y. Yamamoto, Y. Ichise, H. Yamada, K. Akashi, et al. "SAT0011 COMBINED INHIBITION OF AUTOPHAGY AND GLUTAMINE METABOLISM SUPPRESSES CELL GROWTH OF RA SYNOVIOCYTES AND AMELIORATES ARTHRITIS IN SKG MICE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 935.2–936. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1661.
Анотація:
Background:Immunometabolism is now recognaized to be crucial in the pathogenesis of rheumatoid arthritis (RA). We have recently shown that the expression of glutaminase 1 (GLS1), a key enzyme in glutaminolysis, is upregulated in fibroblast-like synoviocytes from RA patients (RA-FLS) and that GLS1 inhibition suppresses RA-FLS proliferation (1). However, glutaminolysis has been known to suppress autophagy by activating mTORC1 or counteracting ROS production (2). Given the possibility of autophagy upregulation following glutamiolysis inhibition, therapies targeting both autophagy and glutaminolysis may be more effective in suppressing cell growth of RA-FLS, yet the relation between glutaminolysis and autophagy in RA-FLS has not been investigated.Objectives:To examine the effects of inhibiting both glutaminolysis and autophagy on RA-FLS and autoimmune arthritis in SKG mice.Methods:GLS1 inhibitor, compound 968 (C968), was used to suppress glutaminolysis, and Chloroquine (CQ) was used to inhibit autophagy. To detect autophagy, the expression of ATG5 and LC3B was measured by real-time PCR and the production of LC3-II was analyzed by Western blotting. The formation of autophagic vacuoles was identified by immunfluorescense. Cell growth was evaluated by BrdU assay. Apoptosis was analyzed by flow cytometry staining with Annexin V-FITC and PI. C968 and CQ were administered subcutaneously to Zymosan A-injected SKG mice.Results:C968 upregulated the expression of ATG5 and LC3B, and increased the protein level of LC3-II in RA-FLS. C968 also facilitated autophagosome formation. These results suggested that inhibition of glutaminolysis promoted autophagy in RA-FLS. The combined treatment with C968 and CQ significantly suppressed cell proliferation of RA-FLS more strongly than did C968 or CQ alone. In addition, C968 combined with CQ increased the apoptosis rate, whereas either C968 or CQ alone did not. Furthermore, combination of C968 and CQ significantly attenuated the degree of arthritis in SKG mice, while C968 or CQ monotherapy did not (Figure).Conclusion:The GLS1 inhibitor C968 promotes autophagy in RA-FLS. C968 in combination with CQ reduces proliferation and enhances apoptosis in RA-FLS, and ameliorates the arthritis in SKG mice. Suppressing C968-induced autophagy may be a promising therapy for arthritis.References:[1] Takahashi S., et al. Arthritis Res Ther. 2017 Apr 11;19(1):76.[2] Villar VH., et al. Autophagy. 2015;11(8):1198-208.Acknowledgments :NoneDisclosure of Interests:None declared
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Poonaki, Elham, Ann-Christin Nickel, Mehdi Shafiee Ardestani, Lars Rademacher, Marilyn Kaul, Evgeny Apartsin, Sven G. Meuth, Ali Gorji, Christoph Janiak, and Ulf Dietrich Kahlert. "CD133-Functionalized Gold Nanoparticles as a Carrier Platform for Telaglenastat (CB-839) against Tumor Stem Cells." International Journal of Molecular Sciences 23, no. 10 (May 13, 2022): 5479. http://dx.doi.org/10.3390/ijms23105479.
Анотація:
The failure of a long-lasting curative therapeutic benefit of currently applied chemotherapies against malignant cancers is suggested to be caused by the ineffectiveness of such interventions on cancer stem cells (CSCs). CD133/AC133 is a cell surface protein previously shown to have potential to identify CSCs in various tumors, including brain tumors. Moreover, an increase in the rate of cellular metabolism of glutamine and glucose are contributors to the fast cellular proliferation of some high-grade malignancies. Inhibition of glutaminolysis by utilizing pharmacological inhibitors of the enzyme glutaminase 1 (GLS1) can be an effective anti-CSC strategy. In this study, the clinical-stage GLS1 inhibitor Telaglenastat (CB-839) was loaded into PEGylated gold nanoparticles equipped with the covalently conjugated CD133 aptamer (Au-PEG-CD133-CB-839) and exposed to a collection of CD133-positive brain tumor models in vitro. Our results show that Au-PEG-CD133-CB-839 significantly decreased the viability of CD133-postive cancer cells in a dose-dependent manner, which was higher as compared to the effects of treatment of the cells with the individual components of the assembled nanodrug. Interestingly, the treatment effect was observed in glioblastoma stem cells modeling different transcriptomic subtypes of the disease. The presented platform is the fundament for subsequent target specificity characterization and in vivo application.
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Xu, Kangdi, Jun Ding, Lingfeng Zhou, Dazhi Li, Jia Luo, Wenchao Wang, Mingge Shang, Bingyi Lin, Lin Zhou, and Shusen Zheng. "SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis." Cells 12, no. 1 (December 21, 2022): 25. http://dx.doi.org/10.3390/cells12010025.
Анотація:
Metabolic reprogramming, such as alterations in glutamine metabolism or glycolysis, is the hallmark of hepatocellular carcinoma (HCC). However, the underlying mechanisms are still incompletely elucidated. Previous studies have identified that methyltransferase SET and MYND domain-containing protein 2(SMYD2) is responsible for the pathogenesis of numerous types of cancer. Here, we innovatively uncover how SMYD2 regulates glutamine metabolism in HCC cells and promotes HCC progression. We identified that SMYD2 expression is upregulated in HCC tissues, which correlates with unfavorable clinical outcomes. Our in vitro and in vivo results showed that the depletion of SMYD2 inhibits HCC cell growth. Mechanistically, c-Myc methylation by SMYD2 increases its protein stability through the ubiquitin–proteasome system. We showed SMYD2 depletion destabilized c-Myc protein by increasing the conjugated K48-linked polyubiquitin chain. SMYD2 increased c-Myc expression and further upregulated glutaminase1 (GLS1), a crucial enzyme that catalyzes the conversion of glutamine to glutamic acid, in HCC cells. GLS1 plays an important role in SMYD2-mediated HCC progression and glutamine metabolism regulation. The knockdown of SMYD2 inhibited glutamine metabolism in HCC cells and overcame their chemoresistance to sorafenib. Collectively, our findings demonstrated a novel mechanism of how SMYD2 promotes HCC progression by regulating glutamine metabolism through the c-Myc/ GLS1signaling, implicating the therapeutic potential of targeting SMYD2 in HCC patients.
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Lang, Liwei, Fang Wang, Chloe Shay, Yonggang Ke, Nabil Saba, and Yong Teng. "Abstract 3026: Inhibition of glutaminolysis overcomes metabolic adaptation to devimistat treatment." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3026. http://dx.doi.org/10.1158/1538-7445.am2022-3026.
Анотація:
Abstract The identification and development of reagents that can limit preferential metabolic effectors in tumors as well as trigger unfavorable tumoral metabolic cues is of tremendous importance for suppressing malignancy. However, insufficient blocking of critical metabolic dependencies of cancer allows the development of metabolic bypasses, which significantly dampens therapeutic benefits of selective agents that target a single metabolic enzyme or pathway. We report here that head and neck squamous cell carcinoma (HNSCC) cells display strong addiction to glutamine. Devimistat, a novel lipoate analog, redirects cellular activity towards tumor-promoting glutaminolysis, leading to low anticancer efficacy in HNSCC cells. Mechanistically, devimistatinhibits the tricarboxylic acid cycle by blocking the enzyme activities of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which upregulates GLS1 and eventually promotes the compensatory role of glutaminolysis in cancer cell survival. Most importantly, the addition of a GLS1 inhibitor CB-839 to devimistat treatment abrogates the metabolic dependency of HNSCC cells on glutamine, achieving a synergistic anticancer effect in glutamine-addicted HNSCC. These novel and significant findings could lay a scientific foundation for developing more effective treatments targeting the metabolic requirements of HNSCC. Citation Format: Liwei Lang, Fang Wang, Chloe Shay, Yonggang Ke, Nabil Saba, Yong Teng. Inhibition of glutaminolysis overcomes metabolic adaptation to devimistat treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3026.
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Ozcan, Selahattin C., Aydan Mutlu, Tugba H. Altunok, Yunus Gurpinar, Aybike Sarioglu, Sabire Guler, Robertino J. Muchut, et al. "Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells." Biochemical and Biophysical Research Communications 571 (September 2021): 118–24. http://dx.doi.org/10.1016/j.bbrc.2021.07.070.
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Xi, Jianbo, Yaocheng Sun, Meiting Zhang, Zhenzhong Fa, Yanya Wan, Zhenyu Min, Hong Xu, Chengkai Xu та Jianjun Tang. "GLS1 promotes proliferation in hepatocellular carcinoma cells via AKT/GSK3β/CyclinD1 pathway". Experimental Cell Research 381, № 1 (серпень 2019): 1–9. http://dx.doi.org/10.1016/j.yexcr.2019.04.005.
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Jo, Michiko, Keiichi Koizumi, Mizuho Suzuki, Daisuke Kanayama, Yurie Watanabe, Hiroaki Gouda, Hisashi Mori, et al. "Design, synthesis, structure–activity relationship studies, and evaluation of novel GLS1 inhibitors." Bioorganic & Medicinal Chemistry Letters 87 (May 2023): 129266. http://dx.doi.org/10.1016/j.bmcl.2023.129266.
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Okada, Takuya, Kaho Yamabe, Michiko Jo, Yuko Sakajiri, Tomokazu Shibata, Ryusuke Sawada, Yoshihiro Yamanishi, et al. "Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity." Bioorganic & Medicinal Chemistry Letters 93 (September 2023): 129438. http://dx.doi.org/10.1016/j.bmcl.2023.129438.
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Lam, Elaine T., Lih-Jen Su, Maren Salzmann-Sullivan, Steven K. Nordeen, and Thomas W. Flaig. "Preclinical evaluation of teleglenastat (CB-839) in prostate cancer." Journal of Clinical Oncology 41, no. 6_suppl (February 20, 2023): 378. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.378.
Анотація:
378 Background: Glutaminase (GLS) levels are upregulated in prostate cancer [PMID: 28138303, 16897757]. The androgen receptor signaling pathway enhances the expression of SLC43A1, SLC1A4 and SLC1A5 (amino acid and glutamine transporters) in prostate cancer cells [PMID: 22007000, 24052624, 28507054]. We evaluated prostate cancer data from The Cancer Genome Atlas and found that GLS expression correlates with Gleason sum. We performed in vitro and in vivo experiments to evaluate the effect CB-839, a glutaminase inhibitor (GLS1 > GLS2), as monotherapy and in combination with other agents. Methods: We evaluated glutamine dependence of 3 prostate cancer cell lines [parental LNCaP (P0, hormone-sensitive), LNCaP-derived castrate resistant (CRPC) variant (P1, PMID: 34575033), and PC-3 (CRPC)] using media with and without glutamine, as well as clonogenic assays in regular media with BPTES (GLS1 inhibitor as a control) and CB-839. Combinatorial treatment and dose response studies were performed with CB-839 plus enzalutamide (ENZ), everolimus (EVE), or olaparib (OLA). We used NOD SCID female nude mice carrying P1 and PC3 prostate tumor xenografts to evaluate effects of CB-839 monotherapy, CB-839 + EVE, and EVE monotherapy. Results: P0, P1, and PC-3 all exhibited glutamine dependence. In glutamine-deplete media, all tested cell lines formed < 50% of colonies from baseline. Clonogenic assays with BPTES showed IC50 of 2-6 uM. CB-839 showed single agent activity in vitro with IC50 = 1 uM (P0), IC50 = 2 (P1), and IC50 < 0.1 uM (PC-3). The IC50 of CB-839 + ENZ in P1 cells was < 4uM CB-839 + 2uM ENZ. CB-839 + OLA showed no additive effect as OLA alone was very active (IC50 < 100 nM) in P1 cells. CB-839 + EVE showed single agent and synergistic effect (IC50 < 4 uM CB-839 + 0.05 uM EVE) in both P1 and PC-3 cells. In P1 tumor xenografts, treatment response was seen in CB-839 monotherapy, EVE monotherapy, and CB-839 + EVE treatment arms. In PC-3 xenografts, treatment response was seen in all groups, with greater effect in the EVE monotherapy and CB-839 + EVE treatment groups compared with CB-839 monotherapy. Conclusions: CB-839, EVE, and CB-839 + EVE all demonstrated activity in P1 and PC-3 castrate resistant prostate cancer tumor xenografts. Additive or synergistic activity was difficult to assess with combination therapy since each drug was effective as monotherapy. Additional studies are needed to evaluate the role of EVE monotherapy or CB-839 + EVE in prostate cancer. Research Sponsors: NCI CTEP UM1 Supplement CA186688-04, NCI University of Colorado Cancer Center Support Grant 5P30CA046934-30. [Table: see text]
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Li, Lingzhi, Changying Jiang, Lucy Jayne Navsaria, Yang Liu, Angela Leeming, Michael Wang, and Yixin Yao. "Targeting Glutamine Metabolism Overcomes Resistance to Targeted Therapies in Refractory Mantle Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 25–26. http://dx.doi.org/10.1182/blood-2020-140736.
Анотація:
Background: Mantle cell lymphoma (MCL) is an incurable B cell non-Hodgkin's lymphoma characterized by high refractory occurrence following drug treatment. Despite the encouraging initial MCL tumor response to ibrutinib (IBN), relapse occurs only after few months of treatment due to multiple resistance mechanisms. Thus, the novel therapeutic strategies targeting resistant mechanisms are crucial. Our group has recently shown that among the highly proliferative MCL population, a subpopulation of IBN-R cells exhibits increased OXPHOS activity that is fueled by increased glutaminolysis and rely more on mitochondrial respiration for their grow and survival. The aim of this work was to uncover potential targets responsible for the upregulation of OXPHOS pathway in the refractory/relapsed (R/R) MCL by using multiple biochemical and biological strategies. We focused the present study on glutaminase (GLS), the enzyme that converts glutamine to glutamate, a precursor of α-ketoglutarate (α-KG) that links glutamate to the TCA cycle. Incorporation of α-KG into the TCA cycle is a major anaplerotic step in proliferating cells and is critical for the maintenance of TCA cycle function. To further demonstrate the reliance of OXPHOS on glutamine anaplerosis, we have further tested the combinatory effects of targeting GLS and OXPHOS using their respective inhibitors, CB-839 and IACS-010759, on tumor killing activity in R/R MCL. Methods:Primary MCL cells from patient leukapheresis or whole blood specimens, as well as established MCL cell lines were used as experimental models of MCL. Metabolomic profiling was used to determine intracellular metabolite fluxes and levels. Cell Titer Glo assay was used to measure cell proliferation/viability after treatment with inhibitors. Annexin V and propidium iodide were used to measure cell apoptosis and cell cycle arrestviaflow cytometry analysis. Magnetic microbeads-based B-cell isolation method were used for the purification of malignant B cells from patient samples. Western blot analysis was used to evaluate protein level expression. Patient-derived Xenograft (PDX) mouse model created from patients with MCL was used to evaluate the in vivo anti-tumor activity and potential clinical value of GLS and OXPHOS inhibitors. Results:Our recent metabolomic profiling studies have demonstrated that glutaminolysis and OXPHOS are upregulated in IBN-R MCL, manifested by increased glutamine uptake in the ibrutinib-resistant MCL cell lines (p=0.03).Inhibition of glutamine metabolism with the allosteric GLS1-selective inhibitor BPTES resulted in inhibition of cell viability (0.2381uM-9.98uM), indicating that MCL cells are dependent on glutamine metabolism for their proliferation. To corroborate with the above finding, we also presented evidence that GLS1 is highly increased in IBN-R and CART-R MCL patient samples and cell lines confirmed by immunoblotting. Inhibiting of GLS would lead to significant reduction in OXPHOS, mitochondria membrane potential and ATP production, as either single drug or in combination with other targeting agents. To identify a clinical actionable GLS inhibitor for the treatment of MCL, we chose a GLS1 specific inhibitor CB-839 (Selleckchem), currently under several phase II and III clinical trials investigation on solid tumors. Inhibiting GLS1 with CB-839 leads to the decreased cell viability in MCL (0.5626nM-308.4nM). Of note, the treatment with CB-839 to MCL cell lines induces S phase reduction in both Jeko-1 (17.23%) and Z-138 (14.01%), as well as induces significant apoptosis (p=0.013 and p=0.002 in Jeko-1 and Z-138 cells). GLS inhibition will be further explored in the context of mitochondria defect or hypoxia, where OXPHOS maybe deficient. Importantly, while CB-839 is continuing its validation in several solid tumor models, this is the first study providing data on its efficacy in preclinical models of MCL. Conclusion:In conclusion, we report that glutaminolysis and OXPHOS are upregulated in IBN-R MCL that could be partially due to high expression of GLS1. Our preliminary results revealed that the new GLS inhibitor, GCB-839, may present a clinical potential for a new indication and warrants more in-depth investigation. Deciphering the mechanisms involved in MCL metabolic heterogeneity and adaptability during drug resistance development would be crucial to identify key actors enabling MCL cells to escape from therapy. Disclosures Wang: Acerta Pharma:Research Funding;Molecular Templates:Research Funding;InnoCare:Consultancy;Oncternal:Consultancy, Research Funding;Celgene:Consultancy, Other: Travel, accommodation, expenses, Research Funding;Targeted Oncology:Honoraria;MoreHealth:Consultancy;Kite Pharma:Consultancy, Other: Travel, accommodation, expenses, Research Funding;Lu Daopei Medical Group:Honoraria;OMI:Honoraria, Other: Travel, accommodation, expenses;Verastem:Research Funding;Nobel Insights:Consultancy;BioInvent:Research Funding;Guidepoint Global:Consultancy;AstraZeneca:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Pharmacyclics:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Janssen:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Juno:Consultancy, Research Funding;Dava Oncology:Honoraria;Loxo Oncology:Consultancy, Research Funding;Pulse Biosciences:Consultancy;OncLive:Honoraria;Beijing Medical Award Foundation:Honoraria;VelosBio:Research Funding.
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Moncada, Salvador, E. Annie Higgs, and Sergio L. Colombo. "Fulfilling the metabolic requirements for cell proliferation." Biochemical Journal 446, no. 1 (July 27, 2012): 1–7. http://dx.doi.org/10.1042/bj20120427.
Анотація:
The activity of key metabolic enzymes is regulated by the ubiquitin ligases that control the function of the cyclins; therefore the activity of these ubiquitin ligases explains the coordination of cell-cycle progression with the supply of substrates necessary for cell duplication. APC/C (anaphase-promoting complex/cyclosome)-Cdh1, the ubiquitin ligase that controls G1- to S-phase transition by targeting specific degradation motifs in cell-cycle proteins, also regulates the glycolysis-promoting enzyme PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3) and GLS1 (glutaminase 1), a critical enzyme in glutaminolysis. A decrease in the activity of APC/C-Cdh1 in mid-to-late G1 releases both proteins, thus explaining the simultaneous increase in the utilization of glucose and glutamine during cell proliferation. This occurs at a time consistent with the point in G1 that has been described as the nutrient-sensitive restriction point and is responsible for the transition from G1 to S. PFKFB3 is also a substrate at the onset of S-phase for the ubiquitin ligase SCF (Skp1/cullin/F-box)-β-TrCP (β-transducin repeat-containing protein), so that the activity of PFKFB3 is short-lasting, coinciding with a peak in glycolysis in mid-to-late G1, whereas the activity of GLS1 remains high throughout S-phase. The differential regulation of the activity of these proteins indicates that a finely-tuned set of mechanisms is activated to fulfil specific metabolic demands at different stages of the cell cycle. These findings have implications for the understanding of cell proliferation in general and, in particular, of cancer, its prevention and treatment.
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Matre, Polina, Ismael Samudio, Rodrigo Jacamo, Ying Wang, Jing Wang, R. Eric Davis, Xiaohua Su, et al. "Unraveling The Molecular and Metabolic Basis For Glutamine Addiction In Leukemias." Blood 122, no. 21 (November 15, 2013): 606. http://dx.doi.org/10.1182/blood.v122.21.606.606.
Анотація:
Abstract The bone marrow (BM) microenvironment is characterized by hypoxia and the presence of supporting mesenchymal stromal cells (MSC) that promote leukemia cell survival and resistance to therapy, in part by metabolic reprogramming. However mechanisms that couple leukemic cells survival to metabolic processes under different microenvironment conditions have not been elucidated. Glutamine (Gln) provides cells with carbon skeletons to the Krebs cycle (KC) via anaplerosis, sustains cell proliferation, regulates redox homeostasis and modulates activity of signal transduction pathways. Recent data suggests that leukemia cells reduce molecular oxygen utilizing electrons from carbon sources other than pyruvate, and we hypothesize that these electrons could be provided at least in part by glutaminolysis. Our recent studies utilizing gene expression profiling indicate that MSC co-culture under hypoxia promoted glycolytic gene expression in AML cells, as well as genes regulating oxidative phosphorylation (OXPHOS), KC cycle and Gln utilization (GLS1, GOT) (Matre et al., AACR 2013:1887). Here we report studies aimed to unravel metabolic changes in proliferating leukemic cells under hypoxia and upon interaction with MSC and determine the role of Gln as a contributor. First, we performed GC-MS metabolic profiling of OCI-AML3 leukemic cells alone or in co-cultured with MSC under hypoxic or normoxic conditions and observed significant changes in the core metabolic processes. Our data demonstrates that microenvironment promotes glucose-independent OXPHOS to meet bioenergetics needs of leukemic cells. Interaction with MSC propels a glucose-independent oxidative KC through Gln and asparagine catabolism even under conditions where oxygen concentration is limited. Under hypoxia, concentrations of KC intermediates were lower compared to normoxia, however the accumulation of 2-hydroxyglutarate suggests reverse KC activity with glutamate-derived 2-oxoglutarate being converted to citrate via reductive carboxylation pathway. In addition, consumption of glucogenic amino acids was upregulated by MSCs. Glycolytic intermediates accumulated under hypoxia and coculture accompanied by excretion of pyruvate as lactate, suggesting increased availability of carbon skeletons for biomass generation provided, in part, by glutaminolysis. Next, oxygen consumption rates (OCR) and extra-cellular acidification rates (ECAR) in OCI-AML3 and REH cells were assayed using Seahorse Bioscience XF96 EF Analyzer (Billerica, MA). Glutaminase (GLS) inhibition by BPTES or shRNA caused a decrease in basal OCR, reduced ATP production and decreased maximal respiratory capacity of leukemic cells (Fig. 1). Both acute and prolonged exposure to BPTES resulted in a compensatory increase in glycolytic activity as shown by increase in ECAR and confirmed by media lactate levels.Fig. 1OCR in AML and ALL after BPTES treatment.Fig. 1. OCR in AML and ALL after BPTES treatment. Analysis of a panel of acute leukemia cell lines (n=12) showed that subset of leukemia (75%) markedly dependent on Gln for growth with Gln deprivation causing steep decrease in viable cell number via induction of apoptosis. In addition, in the corresponding subset, inhibition of GLS (GLS1) with BPTES decreased cell growth and increased apoptosis under both normoxia and hypoxia. Notably, MSC co-culture failed to protect firmly attached hypoxic AML cells, which are otherwise resistant to chemotherapy-induced cytotoxicity. Finally, the expression of GLS1 gene splice variants, Glutaminase C (GAC) and kidney glutaminase (KGA), was determined using oligonucleotide microarrays (HG U133 Plus 2.0, Affymetrix) in 288 AML and in 103 normal samples (healthy BM and non-leukemia conditions, Haferlach, JCO 2010). GAC transcript was found to be significantly overexpressed in several AML subtypes, including AML with FLT3 gene mutations and complex cytogenetics. In turn, KGA expression was not different between AML and normal samples. In summary, our results indicate that Gln is a major source of carbon skeletons for KC activity in AML cells, and demonstrate the key role of Gln utilization pathway for the survival of hypoxic BM-resident leukemic cells and “Glutamine-dependent OXPHOS subset” of leukemia. These findings support the notion of targeting microenvironment-fueled leukemia metabolism through pharmacological inhibition of GLS with novel selective GLS1/2 inhibitors entering clinical arena. Disclosures: No relevant conflicts of interest to declare.
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Wu, Shuai, Takeshi Fukumoto, Jianhuang Lin, Timothy Nacarelli, Yemin Wang, Dionzie Ong, Heng Liu, et al. "Targeting glutamine dependence through GLS1 inhibition suppresses ARID1A-inactivated clear cell ovarian carcinoma." Nature Cancer 2, no. 2 (January 11, 2021): 189–200. http://dx.doi.org/10.1038/s43018-020-00160-x.
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Cai, Wei-Feng, Cixiong Zhang, Yu-Qing Wu, Gui Zhuang, Zhiyun Ye, Chen-Song Zhang, and Sheng-Cai Lin. "Glutaminase GLS1 senses glutamine availability in a non-enzymatic manner triggering mitochondrial fusion." Cell Research 28, no. 8 (June 22, 2018): 865–67. http://dx.doi.org/10.1038/s41422-018-0057-z.
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Gao, Chuan-Cheng, Qin-Qin Xu, Feng-Jun Xiao, Hua Wang, Chu-Tse Wu, and Li-Sheng Wang. "NUDT21 suppresses the growth of small cell lung cancer by modulating GLS1 splicing." Biochemical and Biophysical Research Communications 526, no. 2 (May 2020): 431–38. http://dx.doi.org/10.1016/j.bbrc.2020.03.089.
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Henry, Christophe, Dimitri Gorge-Bernat, Pascal Pannier, Isabelle Meaux, Jane Cheng, Fangxian Sun, Olivier Pasquier, et al. "Abstract 6033: RA123, a new GLS1 allosteric inhibitor demonstrates in vitro and in vivo activity in multiple myeloma models." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6033. http://dx.doi.org/10.1158/1538-7445.am2023-6033.
Анотація:
Abstract The conditional essential amino acid glutamine is utilized by tumors to sustain bioenergetic requirements in a nutrient-poor microenvironment. Based on this specific tumor need, efforts have been made to target the glutamine metabolism using glutaminase inhibitors. In this study, we present in vitro and in vivo studies demonstrating activities and target engagement of a new specific GLS1 allosteric inhibitor (RA123). In vitro, RA123 was tested in imid-resistant, CD38 low RPMI8226 multiple myeloma cell line using the ATP Cell titer Glo assay over a 72h treatment period. In vivo, RA123 was tested in mice xenografted with RPMI8226 multiple myeloma cell line. Compound was given at three different under a BID (twice a day) regimen. Tumor growth under treatment was monitored by caliper measurement for 20 days. A terminal PK/PD study on the same model was setup measuring impact of the drug on the glutamine and glutamate tumor content post 24 hours after the last administration. Over the same period, PK measurements were planned to document drug exposure in the plasma and in the tumor. Finally, in a stand-alone study, target engagement was documented using imaging modality. [18F]FSPG PET radiotracer was used to visualize and quantify impact of RA123 on tumor (RPMI8226) glutamate pool. RA123 was given at three doses under a BID regimen. Treatment was administered for 3 days, and PET signal was recorded at baseline and at end of day 3. In vitro study demonstrated that RA123 was able to induce cell killing of RPMI8226 after 72 hours of treatment. These data translated in vivo by a dose-dependent effect on cell growth. In a terminal PK/PD study, RA123 confirmed a dose-dependent impact on glutamine and glutamate tumor levels which correlated with both plasma and tumor exposure. Further confirmation of target engagement was observed with reduced PET uptake post- RA123 treatment at the three doses tested. In conclusion, this study demonstrated that RA123, a new specific GLS1 allosteric inhibitor was able to impact multiple myeloma tumor cell growth both in vitro and in vivo. This effect was associated with reduced glutamate pools and accumulation of glutamine levels within the tumor cells. Citation Format: Christophe Henry, Dimitri Gorge-Bernat, Pascal Pannier, Isabelle Meaux, Jane Cheng, Fangxian Sun, Olivier Pasquier, Philippe Lienard, Erwan Jouannot, Thierry Gouyon, Geneviève Estenne-Bouhtou, Bailin Zhang, Bérangère Thiers, Laurent Debussche, David Machnik. RA123, a new GLS1 allosteric inhibitor demonstrates in vitro and in vivo activity in multiple myeloma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6033.
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Sponagel, Jasmin, Shanshan Zhang, Jill Jones, Prakash Chinnaiyan, Joshua Rubin, and Joseph Ippolito. "TAMI-37. SEX DIFFERENCES IN REDOX STATE UNDERLIE GLUTAMINE DEPENDENCY IN MALE GLIOBLASTOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii221. http://dx.doi.org/10.1093/neuonc/noaa215.925.
Анотація:
Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. GBM occurs more commonly in males but female patients survive significantly longer. Understanding the molecular mechanisms underlying this clinical sex disparity could support novel treatment strategies to improve outcomes for GBM patients. In this regard, we found that male and female GBM patient tissues differ in their metabolite profiles and that male GBM exhibit a higher abundance of amino acid metabolites. We confirmed these findings in a murine model of GBM. Furthermore, we found that male GBM cells are more sensitive to amino acid deprivation. This male-specific dependency on amino acids is almost entirely driven by amino acids involved in the synthesis of the antioxidant glutathione. Glutaminase 1 (GLS1) mediates the conversion from glutamine to glutamate, a crucial component of glutathione. We found that male GBM cells are more sensitive to GLS1 inhibition with the clinical inhibitor CB-839. This correlated with significantly increased reactive oxygen species (ROS) in male GBM. We further confirmed sex differences in redox state through pharmacological depletion of glutathione, which resulted in a significant increase in ROS and cell death in male GBM cells. Moreover, assays of glutathione oxidation demonstrated that male GBM cells exist in a chronically oxidized state. Finally, we found that mitochondrial structure and function, including TCA cycle flux, NADH levels, and antioxidant activity, differ between male and female GBM cells. Together, these data suggest that (1) male and female GBM differ in their amino acid requirements, (2) male GBM are more dependent on glutamine to regulate ROS levels, and (3) sex differences in mitochondrial physiology may result in ROS accumulation and increased susceptibility to drugs targeting the redox state in male GBM. Our data reveal novel metabolic targets for GBM and underline the importance of considering sex in metabolic targeting approaches.