Academic literature on the topic 'Metabolism, Cell Cycle, Cancer, Kras'
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Journal articles on the topic "Metabolism, Cell Cycle, Cancer, Kras"
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Chiu, Ching-Feng, Ming-I. Hsu, Hsiu-Yen Yeh, Ji Min Park, Yu-Shiuan Shen, Te-Hsuan Tung, Jun-Jie Huang, Hung-Tsung Wu, and Shih-Yi Huang. "Eicosapentaenoic Acid Inhibits KRAS Mutant Pancreatic Cancer Cell Growth by Suppressing Hepassocin Expression and STAT3 Phosphorylation." Biomolecules 11, no. 3 (March 2, 2021): 370. http://dx.doi.org/10.3390/biom11030370.
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Background: The oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation was reported to be the signature genetic event in most cases of pancreatic ductal adenocarcinoma (PDAC). Hepassocin (HPS/FGL1) is involved in regulating lipid metabolism and the progression of several cancer types; however, the underlying mechanism of HPS/FGL1 in the KRAS mutant PDAC cells undergoing eicosapentaenoic acid (EPA) treatment remains unclear. Methods: We measured HPS/FGL1 protein expressions in a human pancreatic ductal epithelial (HPNE) normal pancreas cell line, a KRAS-wild-type PDAC cell line (BxPC-3), and KRAS-mutant PDAC cell lines (PANC-1, MIA PaCa-2, and SUIT-2) by Western blot methods. HEK293T cells were transiently transfected with corresponding KRAS-expressing plasmids to examine the level of HPS expression with KRAS activation. We knocked-down HPS/FGL1 using lentiviral vectors in SUIT-2 cells and measured the cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenicity assays. Furthermore, a lipidomic analysis was performed to profile changes in lipid metabolism after HPS/FGL1 knockdown. Results: We found that the HPS/FGL1 level was significantly upregulated in KRAS-mutated PDAC cells and was involved in KRAS/phosphorylated (p)-signal transduction and activator of transcription 3 (STAT3) signaling, and the knockdown of HPS/FGL1 in SUIT-2 cells decreased cell proliferation through increasing G2/M cell cycle arrest and cyclin B1 expression. In addition, the knockdown of HPS/FGL1 in SUIT-2 cells significantly increased omega-3 polyunsaturated fatty acids (PUFAs) and EPA production but not docosahexaenoic acid (DHA). Moreover, EPA treatment in SUIT-2 cells reduced the expression of de novo lipogenic protein, acetyl coenzyme A carboxylase (ACC)-1, and decreased p-STAT3 and HPS/FGL1 expressions, resulting in the suppression of cell viability. Conclusions: Results of this study indicate that HPS is highly expressed by KRAS-mutated PDAC cells, and HPS/FGL1 plays a crucial role in altering lipid metabolism and increasing cell growth in pancreatic cancer. EPA supplements could potentially inhibit or reduce ACC-1-involved lipogenesis and HPS/FGL1-mediated cell survival in KRAS-mutated pancreatic cancer cells.
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Hatipoglu, Ahmet, Deepak Menon, Talia Levy, Maria A. Frias, and David A. Foster. "Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells." PLOS ONE 17, no. 10 (October 21, 2022): e0276579. http://dx.doi.org/10.1371/journal.pone.0276579.
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Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid–a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt–a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase–indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas.
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Conroy, Lindsey R., Susan Dougherty, Traci Kruer, Stephanie Metcalf, Pawel Lorkiewicz, Liqing He, Xinmin Yin, et al. "Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo." Cancers 12, no. 1 (January 17, 2020): 237. http://dx.doi.org/10.3390/cancers12010237.
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Dysregulated metabolism is a hallmark of cancer cells and is driven in part by specific genetic alterations in various oncogenes or tumor suppressors. The retinoblastoma protein (pRb) is a tumor suppressor that canonically regulates cell cycle progression; however, recent studies have highlighted a functional role for pRb in controlling cellular metabolism. Here, we report that loss of the gene encoding pRb (Rb1) in a transgenic mutant Kras-driven model of lung cancer results in metabolic reprogramming. Our tracer studies using bolus dosing of [U-13C]-glucose revealed an increase in glucose carbon incorporation into select glycolytic intermediates. Consistent with this result, Rb1-depleted tumors exhibited increased expression of key glycolytic enzymes. Interestingly, loss of Rb1 did not alter mitochondrial pyruvate oxidation compared to lung tumors with intact Rb1. Additional tracer studies using [U-13C,15N]-glutamine and [U-13C]-lactate demonstrated that loss of Rb1 did not alter glutaminolysis or utilization of circulating lactate within the tricarboxylic acid cycle (TCA) in vivo. Taken together, these data suggest that the loss of Rb1 promotes a glycolytic phenotype, while not altering pyruvate oxidative metabolism or glutamine anaplerosis in Kras-driven lung tumors.
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Rana, Manjul, Rita G. Kansal, Jie Fang, Benjamin T. Allen, Jun Yang, and Evan S. Glazer. "Abstract B044: Bromodomain and Extra-Terminal Protein inhibition decreases pancreatic cancer proliferation via MYC-independent pathways." Cancer Research 82, no. 22_Supplement (November 15, 2022): B044. http://dx.doi.org/10.1158/1538-7445.panca22-b044.
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Abstract Introduction: The bromodomain and extra-terminal (BET) protein family contains proteins which have evolutionarily conserved bromodomains (BRDs) that specifically recognize acetylated lysine residues on the histone tails of chromatin and regulate gene transcription. Deregulation of these BRD-containing proteins has been seen in carcinogenesis as they are also known to play role in the regulation of the cell-cycle and MYC oncogenes. BMS-986158 is an oral BET inhibitor which has been used in the clinical trials for both hematologic and advanced solid tumor cancers. We hypothesized that BET inhibition (BETi) decreases pancreatic ductal adenocarcinoma (PDA) proliferation. Methods: Pancreatic cancer cell lines and patient-derived cell-lines (PDCLs) were treated with 2.5 to 100nM BMS-986158 for 72 hours to study dose-response effect with Incucyte. We performed RNA-seq, qPCR, protein analysis, and flow cytometry to evaluate comprehensive changes and underlying mechanisms/pathways including epithelial to mesenchymal transition (EMT) and the cancer stem cell (CSC) phenotype. Various doses of BMS-986158 were used in PDCL and PDA patient-derived organoids (PDO) in combination with chemotherapy drug to evaluate combinational effects. Results: We found that BETi induced dose-dependent decrease in growth of PDA and PDCLs and induced cancer cell death. BETi demonstrated PDO growth inhibition which was enhanced when combined with gemcitabine and paclitaxel chemotherapy. Next, we found that BETi did not affect MYC expression but decreased expression of the SNAI1 (a mesenchymal marker) protein and increased E-cadherin protein expression in PDA cell line and PDO consistent with decreased activation of an EMT program. BETi also decreased expression of CD133, a marker of CSCs in PDO. BETi also induced G1/S Phase cell cycle arrest in PDA PDCLs. Furthermore, RNA-seq studies revealed that BETi treatment inhibits KRAS pathway and upregulates pathways involved in metabolism of lipids and lysosomal degradation. RNA-seq and qPCR demonstrated that GPX3 (glutathione peroxidase 3, a key protein in reactive oxygen species response) gene expression is upregulated in BETi treated samples. Conclusions: Thus, our data demonstrate that BETi through BMS-986158 is an additional therapy for inhibiting PDA growth through mechanisms that are independent of MYC pathway, inhibition of abnormal lipid metabolism and scavenging of reactive oxygen species. Citation Format: Manjul Rana, Rita G. Kansal, Jie Fang, Benjamin T. Allen, Jun Yang, Evan S. Glazer. Bromodomain and Extra-Terminal Protein inhibition decreases pancreatic cancer proliferation via MYC-independent pathways [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B044.
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Renatino-Canevarolo, Rafael, Mark B. Meads, Maria Silva, Praneeth Reddy Sudalagunta, Christopher Cubitt, Gabriel De Avila, Raghunandan R. Alugubelli, et al. "Dynamic Epigenetic Landscapes Define Multiple Myeloma Progression and Drug Resistance." Blood 136, Supplement 1 (November 5, 2020): 32–33. http://dx.doi.org/10.1182/blood-2020-142872.
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Multiple myeloma (MM) is an incurable cancer of bone marrow-resident plasma cells, which evolves from a premalignant state, MGUS, to a form of active disease characterized by an initial response to therapy, followed by cycles of therapeutic successes and failures, culminating in a fatal multi-drug resistant cancer. The molecular mechanisms leading to disease progression and refractory disease in MM remain poorly understood. To address this question, we have generated a new database, consisting of 1,123 MM biopsies from patients treated at the H. Lee Moffitt Cancer Center. These samples ranged from MGUS to late relapsed/refractory (LR) disease, and were comprehensively characterized genetically (844 RNAseq, 870 WES, 7 scRNAseq), epigenetically (10 single-cell chromatin accessibility, scATAC-seq) and phenotypically (537 samples assessed for ex vivo drug resistance). Mutational analysis identified putative driver genes (e.g. NRAS, KRAS) among the highest frequent mutations, as well as a steady increase in mutational load across progression from MGUS to LR samples. However, with the exception of KRAS, these genes did not reach statistical significance according to FISHER's exact test between different disease stages, suggesting that no single mutation is necessary or sufficient to drive MM progression or refractory disease, but rather a common "driver" biology is critical. Pathway analysis of differentially expressed genes identified cell adhesion, inflammatory cytokines and hematopoietic cell identify as under-expressed in active MM vs. MGUS, while cell cycle, metabolism, DNA repair, protein/RNA synthesis and degradation were over-expressed in LR. Using an unsupervised systems biology approach, we reconstructed a gene expression map to identify transcriptomic reprogramming events associated with disease progression and evolution of drug resistance. At an epigenetic regulatory level, these genes were enriched for histone modifications (e.g. H3k27me3 and H3k27ac). Furthermore, scATAC-seq confirmed genome-wide alterations in chromatin accessibility across MM progression, involving shifts in chromatin accessibility of the binding motifs of epigenetic regulator complexes, known to mediate formation of 3D structures (CTCF/YY1) of super enhancers (SE) and cell identity reprograming (POU5F1/SOX2). Additionally, we have identified SE-regulated genes under- (EBF1, RB1, SPI1, KLF6) and over-expressed (PRDM1, IRF4) in MM progression, as well as over-expressed in LR (RFX5, YY1, NBN, CTCF, BCOR). We have found a correlation between cytogenetic abnormalities and mutations with differential gene expression observed in MM progression, suggesting groups of genetic events with equivalent transcriptomic effect: e.g. NRAS, KRAS, DIS3 and del13q are associated with transcriptomic changes observed during MGUS/SMOL=>active MM transition (Figure 1). Taken together, our preliminary data suggests that multiple independent combinations of genetic and epigenetic events (e.g. mutations, cytogenetics, SE dysregulation) alter the balance of master epigenetic regulatory circuitry, leading to genome-wide transcriptional reprogramming, facilitating disease progression and emergence of drug resistance. Figure 1: Topology of transcriptional regulation in MM depicts 16,738 genes whose expression is increased (red) or decreased (green) in presence of genetic abnormality. Differential expression associated with (A) hotspot mutations and (B) cytogenetic abnormalities confirms equivalence of expected pairs (e.g. NRAS and KRAS, BRAF and RAF1), but also proposes novel transcriptomic dysregulation effect of clinically relevant cytogenetic abnormalities, with yet uncharacterized molecular role in MM. Figure 1 Disclosures Kulkarni: M2GEN: Current Employment. Zhang:M2GEN: Current Employment. Hampton:M2GEN: Current Employment. Shain:GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; AbbVie: Research Funding; Takeda: Honoraria, Speakers Bureau; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive: Consultancy, Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Siqueira Silva:AbbVie: Research Funding; Karyopharm: Research Funding; NIH/NCI: Research Funding.
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Liu, Xiaoling, Yichen Jia, Changyuan Shi, Dechen Kong, Yuanming Wu, Tiantian Zhang, Anjie Wei, and Dan Wang. "CYP4B1 is a prognostic biomarker and potential therapeutic target in lung adenocarcinoma." PLOS ONE 16, no. 2 (February 16, 2021): e0247020. http://dx.doi.org/10.1371/journal.pone.0247020.
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CYP4B1 belongs to the mammalian CYP4 enzyme family and is predominantly expressed in the lungs of humans. It is responsible for the oxidative metabolism of a wide range of endogenous compounds and xenobiotics. In this study, using data from The Cancer Genome Atlas (TCGA) project and the Gene Expression Omnibus (GEO) database, a secondary analysis was performed to explore the expression profile of CYP4B1, as well as its prognostic value in patients with lung adenocarcinoma (LUAD). Based on the obtained results, a significantly decreased CYP4B1 expression was discovered in patients with LUAD when compared with their normal counterparts (p<0.05), and was linked to age younger than 65 years (p = 0.0041), history of pharmaceutical (p = 0.0127) and radiation (p = 0.0340) therapy, mutations in KRAS/EGFR/ALK (p = 0.0239), and living status of dead (p = 0.0026). Survival analysis indicated that the low CYP4B1 expression was an independent prognostic indicator of shorter survival in terms of overall survival (OS) and recurrence-free survival (RFS) in patients with LUAD. The copy number alterations (CNAs) and sites of cg23440155 and cg23414387 hypermethylation might contribute to the decreased CYP4B1 expression. Gene set enrichment analysis (GSEA) suggested that CYP4B1 might act as an oncogene in LUAD by preventing biological metabolism pathways of exogenous and endogenous compounds and enhancing DNA replication and cell cycle activities. In conclusion, CYP4B1 expression may serve as a valuable independent prognostic biomarker and a potential therapeutic target in patients with LUAD.
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Dellinger, Thanh Hue, Xiwei Wu, Hyejin Cho, Winnie S. Liang, Ernest Soyoung Han, Mark Tsuneo Wakabayashi, Stephen Lee, et al. "Whole transcriptome changes correlate to exceptional ovarian cancer responders: A sub-analysis of a HIPEC Phase I trial." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 6060. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.6060.
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6060 Background: Advanced stage ovarian cancer patients benefit from hyperthermic intraperitoneal chemotherapy (HIPEC), prolonging overall survival by nearly 12 months. However, molecular changes triggered by HIPEC are not well characterized, and no molecular signatures of response are known. We analyzed early gene expression changes after HIPEC treatment in ovarian tumors. Methods: This is an interval subgroup analysis of a single institution Phase I trial using HIPEC with cisplatin 75 mg/m2 at time of optimal cytoreduction. Snap-frozen biopsies from tumor and normal peritoneum from 20 patients with ovarian cancer before and after HIPEC underwent whole-transcriptome sequencing using Illumina’s NovaSeq 6000 for paired 100 base-pair reads. Differential expression analysis comparing post and pre-samples was done to identify significantly changed genes, and pathway analysis was conducted using GSEA. Results: Sixty-three genes were differentially expressed (P < 0.05, fold change ≥2) between pre- and post-HIPEC tumors. Hierarchical clustering analysis of these genes confirmed that all tumors and normal tissues clustered based on pre-HIPEC versus post-HIPEC status, and not based on their patient source. Gene set enrichment analysis using a collection of 50 “hallmark” gene sets revealed that post-HIPEC tumors demonstrate significant upregulation in immune pathways (TNFA signaling via NFKB, coagulation, complement), followed by epithelial-mesenchymal transition, inflammation, apoptosis, hypoxia, angiogenesis, KRAS signaling and JAK/STAT3 signaling. In contrast, post-HIPEC normal tissues exhibited upregulation in cell cycle pathways (Myc targets V2, G2M checkpoint). As expected, both post-HIPEC tumor and normal samples shared upregulation of genes related to inflammatory response. Lastly, post-HIPEC normal samples revealed downregulation of growth and metabolism pathways; in contrast, cell cycle or DNA repair pathways were downregulated in post-HIPEC tumors. Two exceptional-responders with recurrent platinum-sensitive disease (ongoing PFS 47 and 12+ months) demonstrated the most substantial changes in gene expression. Conclusions: Exceptional ovarian cancer responders to HIPEC are characterized by extensive gene expression changes; specifically, early HIPEC-induced molecular changes are strongly associated with immune pathways changes, implicating a role for immunotherapy after HIPEC in ovarian cancer. Clinical trial information: NCT01970722.
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Ross, P. M. "Cellular and adenovirus dl312 DNA metabolism in cycling or mitotic human cultures exposed to supralethal gamma radiation." Journal of Cell Biology 109, no. 5 (November 1, 1989): 1993–2002. http://dx.doi.org/10.1083/jcb.109.5.1993.
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Cellular repair of DNA damage due to lethal gamma irradiation was studied to reveal differences between strains and cell cycle stages that are otherwise difficult to detect. Cycling and metaphase-blocked cultures of normal fibroblasts and carcinoma cells were compared for repair of gamma sites (gamma radiation-induced nicks, breaks, and alkalilabile sites in DNA) at supralethal exposures ranging from 7 to 150 krad 137Cs radiation and at postirradiation incubations of 20-180 min. Fibroblasts from normal human skin or lung repaired gamma sites efficiently when cycling but did not repair them when blocked at mitosis. Bladder (253J) or lung (A549) carcinoma cells, unlike normal fibroblasts, repaired gamma sites efficiently even when blocked at mitosis. HeLa cells degraded their DNA soon after exposure at all doses tested, regardless of mitotic arrest. Whether the above differences in DNA repair between cell cycle stages and between strains result from differences in chromatin structure (cis effects) or from differences in the nuclear enzymatic environment (trans effects) could be resolved by placing an inert, extrachromosomal DNA molecule in the cell nucleus. Specifically, cis effects should be confined to the host chromosomes and would not be detected in the inert probe whereas trans effects should be detected in host chromosomes and inert probe DNA alike. Indeed, we found a suitable DNA molecule in the adenovirus deletion mutant dl312, which does not proliferate in the absence of E1A complementation. Gamma sites in 32P-labeled adenovirus dl312 DNA were repaired efficiently in all hosts, regardless of mitotic arrest. Failure of mitosis-arrested fibroblasts to repair gamma sites was therefore due to a cis effect of chromatin organization rather than to a trans effect such as repair enzyme insufficiency. In sharp contrast, chromosomes of mitotic carcinoma cells remained accessible to repair enzymes and nucleases alike. By means of these new tools, we should get a better understanding of higher-order chromatin management in normal and cancer cells.
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Boda, Akash, Casey Ager, Kimal Rajapakshe, Spencer Lea, Maria Emilia Di Francesco, Philip Jones, and Michael Curran. "758 High-potency synthetic STING agonists rewire the myeloid stroma in the tumour microenvironment to amplify immune checkpoint blockade efficacy in refractory pancreatic ductal adenocarcinoma." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A793. http://dx.doi.org/10.1136/jitc-2021-sitc2021.758.
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BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is clinically unresponsive to immune checkpoint blockade (ICB) immunotherapy.1 2 High densities of immunosuppressive myeloid cells,3 a paucity of antigen-presenting cells4–6 and T cell exclusion from tumour microenvironment7 all contribute to the refractory nature of PDAC to immune-based therapies. We and others have shown that innate immune activation of myeloid stroma via engagement of the STING (Stimulator of Interferon Genes) pathway can mediate proinflammatory remodeling and trigger a flood of T cell infiltration into otherwise 'cold' tumours.8–11 To that end, intratumoral injection of cyclic dinucleotide (CDN) agonists of the STING pathway has been shown to foster local and abscopal tumor immunity.8–10 Despite proven therapeutic efficacy in preclinical models, the mechanistic basis at a cellular level of how CDNs reprogram the suppressive myeloid stroma to sensitise tumours to ICB is poorly understood.MethodsUsing RNA sequencing and protein arrays we profiled myeloid-derived suppressor cell (MDSC) and M2 macrophage function following stimulation with CDNs of ascending potency. We describe the effects of CDN STING agonists on cell cycle dynamics, metabolic reprogramming and c-Myc expression in MDSCs. Next, in an orthotopic Kras+/G12DTP53+/R172HPdx1-Cre (KPC)-derived model of PDAC, we determined the ability of intratumorally-administered CDNs to sensitise PDAC to checkpoint blockade using bioluminescent in vivo imaging and multi-parameter flow cytometry of tumor stroma post-therapy.ResultsMulti-omics profiling of MDSCs and M2 Macrophages of human and murine origin show that high-potency synthetic STING agonists rewire these populations from immunosuppressive to immune-permissive phenotypes in part through inhibition of c-Myc signaling, energy metabolic modulation, and antagonism of cell cycle. Intratumoral injection of the STING agonist, IACS-8803 resulted in an amplified therapeutic response to checkpoint blockade that was dependent on T/NK cell infiltration into the tumour. Furthermore, dimensionality reduction analyses of multiparameter flow cytometry data show proinflammatory remodeling of the myeloid stroma and enhanced T cell function as salient features of synthetic agonists versus natural CDNs in orchestrating the in vivo therapeutic benefit.ConclusionsThis study uncovers molecular and cellular mechanisms by which STING agonists drive proinflammatory conversion of tumour myeloid stroma. We are the first to report that synthetic CDN STING agonists affect MDSC and M2 macrophage repolarization through altering energy metabolism and c-Myc signalling. Lastly, we demonstrate the potential for high-potency STING agonists to overcome resistance to checkpoint blockade in an aggressive orthotopic tumour model of PDAC.ReferencesRoyal RE, Levy C, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010;33(8):828–33.Brahmer JR, Tykodi SS, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455–65.Karakhanova S, Link J. Characterization of myeloid leukocytes and soluble mediators in pancreatic cancer: importance of myeloid-derived suppressor cells. Oncoimmunology 2015;4:e998519.Dallal RM, Christakos P, et al. Paucity of dendritic cells in pancreatic cancer. Surgery 2002;131:135–138.Yamamoto T, Yanagimoto H, et al. Circulating myeloid dendritic cells as prognostic factors in patients with pancreatic cancer who have undergone surgical resection. J Surg Res 2012;173:299–308.Hegde S, Krisnawan V, et al. Dendritic cell paucity leads to dysfunctional immune surveillance in pancreatic cancer. Cancer Cell 2020;37(3):289–307.Beatty GL, Winograd R, et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages. Gastroenterology 2015;149(1):201–210.Baird JR, Friedman D, et al. Radiotherapy combined with novel STING-Targeting oligonucleotides results in regression of established tumors. Cancer Res 2016;76(1):50–61.Ager CR, Reilley MJ, et al. Intratumoral STING activation with T-cell checkpoint modulation generates systemic antitumor immunity. Cancer Immunol Res 2017;5(8):676–84.Smith TT, Moffett HF, et al. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J Clin Invest 2017;127(6):2176–91.Jing W, McAllister D, et al. STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models. J Immunother Cancer 2019;7(1):115.
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Kalofonos, H. P., A. Antonacopoulou, P. Matsouka, and E. Giannopoulou. "Effect of panitumumab on autophagy in colon cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e22151-e22151. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22151.
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e22151 Background: Panitumumab, a human monoclonal antibody raised against EGFR, has been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of patients with EGFR-expressing mCRC and wild type kras. The ratio of reduced/oxidised form of glutathione (GSH/GSSG) is an indicator of the redox status in cells. The aim of the current study was to investigate the effect of panitumumab on the redox status of colon cancer cell lines Caco-2, DLD-1 and HT-29 regarding proliferation, apoptosis, necrosis, cell cycle arrest and autophagy. Methods: Cell proliferation was measured by MTT assay. Apoptosis and necrosis were detected by annexin v/propidium iodide assay. Cell cycle arrest was estimated by propidium iodide assay. Autophagy was detected by immunobloting and GSH levels were measured by spectrophotometrical analysis. kras mutations were detected by sequencing analysis. Results: Caco-2, DLD-1 and HT-29 cell lines differ in the expression levels of EGFR and HER-2. Kras mutation analysis in previous studies and in the current study showed that DLD-1 cells express mutated kras while Caco-2 and HT-29 cells express wild type of kras. Panitumumab decreased proliferation only in DLD-1 cells 48 h after its application besides the mutated kras. However, panitumumab did not affect DLD-1 cell apoptosis, necrosis or cell cycle progression 24 and 48 h after cells treatment. Interestingly, panitumumab increased protein levels of beclin 1, an indicator of autophagy, 24 h after its addition in cells. Moreover, an increase in GSH levels was noted 48 h after cells treatment with panitumumab. Conclusions: This is the first study to show that panitumumab, an EGFR inhibitor, affects colon cancer cell proliferation independently of kras mutations and EGFR protein levels through the induction of autophagy. The inhibition in cell proliferation was followed by an increase in GSH levels reflecting an imbalance on the redox status of cells. No significant financial relationships to disclose.
Dissertations / Theses on the topic "Metabolism, Cell Cycle, Cancer, Kras"
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GAGLIO, DANIELA. "Role of nutrient availability on proliferation and cell cycle excution of immortalized and kras transformed mouse fibroblastic." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2009. http://hdl.handle.net/10281/7548.
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Mammalian cells proliferate, differentiate or die in response to extracellular signals as growth factors and nutrients. Cancer is essentially a disease in which cells have lost responsiveness to many of these signals and to normal checks on cell proliferation. Therefore, it may not be surprising that tumor cells, in order to meet the increased requirements of proliferation, often display fundamental changes in pathways of energy metabolism and nutrient uptake (Garber, 2006). In particular, several studies shown that the process of tumorigenesis is often associated with altered metabolism of two major nutrients, glucose and glutamine (Mazurek et al, 1998; Chiaradonna et al., 2006; Gaglio et al., 2009). Moreover, this metabolic changes and cellular sensitivity to these nutrients can be induced or influenced by oncogenic transformation as i.e. Ras mutation (Chiaradonna et al., 2006; Gaglio et al., 2009) that has been found in 25% of human cancers.
Glucose and glutamine are involved in multiple pathways required for cell proliferation and survival both in normal and transformed cells. The role of these pathways in the survival of transformed cells is mostly based either from the fact that the pathways in question can be regulated by oncogenes, or that cell death following nutrients shortage is associated with changes in the activation state of these pathways. In particular, in this work has been studied the response of K-Ras transformed cells to glucose and glutamine availability.
Transformed cells have been shown to have a particular dependence on aerobic glycolysis compared to normal cells. Indeed, proliferation analysis of asynchronous K-Ras transformed fibroblasts as compared to normal cells, grown both in high and low glucose (25mM and 1mM), indicated that transformed cells showed an higher proliferation potential in 25mM glucose and lost completely this proliferative advantage in low glucose (1mM). Moreover, the strong reduction of glucose availability, observed at 72hrs in cells grown in 1mM glucose, induced an enhanced apoptosis only in transformed cells. Indeed, the apoptotic process activated in normal cells was glucose independent and probably correlated to prolonged contact inhibition. This effect has been validated by both Annexin V/PI staining and caspases-3 activation. Since transformed cells were characterized by strong reduction of proliferation as well as apoptosis at low glucose concentration, it has been analyzed the effects of Ras activation and glucose shortage on the cell cycle machinery, in particular during G1/S transition in synchronized normal and transformed cells. These results indicated that the timing of G1/S transition execution was glucose independent in both cell lines. Therefore, oncogenic Ras expression is able to induce a greater sensitivity to glucose shortage as compared to normal cells (decreased proliferation and enhanced apoptosis) only if the glucose shortage is persistent.
Another metabolic adaptation of cancer cells, that has been studied, is their propensity to exhibit increased glutamine consumption.
The results indicated that in asynchronous normal cells, contact inhibition, regardless of glutamine availability, brings to down-regulation of Akt that together with AMPK up-regulation, observed at low glutamine, concurs to TOR pathway inactivation. As a result, the expression of cyclin D, E and A is down regulated, pRb phosphorylation is strongly reduced, p27kip1 level is increased and its localization becomes preferentially nuclear, establishing therefore a condition that bring to a G1- cell cycle arrest. In synchronous normal cells, glutamine shortage slows the G2/M transition, indicating a possible role of glutamine in such cell cycle phase.
In K-ras transformed cells, in which the level of activated Ras-GTP is very high (Nagase et al., 1995) and the contact inhibition is less efficient (Nagase et al., 1995), the deprivation of glutamine affects Akt and AMPK in a way opposite to that observed in normal cells, leaving the TOR pathway at least partially activated. This event allows sizable expression of cyclin D (at least until 72 hrs), E and A, sustained pRb phosphorylation, decreased p27kip1 and its preferential cytoplasmic localization, conditions that, taken together, promote entrance into S phase. Surprisingly, in condition of glutamine shortage, transformed asynchronous cells accumulate in S phase. In synchronous transformed cells, glutamine shortage slows both the G1 to S and the G2/M transitions.
Since glutamine is an important intermediate in purine and pyrimidine biosynthesis, glutamine exhaustion could deplete intracellular nucleotide pools, bringing in turn to a failure in the execution of a normal cell cycle (Christofk et al., 2008; Martinez-Diez et al., 2006). This hypothesis has been confirmed by the fact that the proliferation defect of transformed cells is rescued by adding the four deoxyribonucleotides (precursors of DNA polymerization) to low glutamine medium. Moreover, experiments performed in synchronized transformed cells have been shown that low-glutamine medium causes a 2 hrs delay in entering into S phase after serum re-addition. This effect on cell cycle timing is worsened by complete absence of glutamine, in which 4 hrs delay in entering into S phase was observed. These data strongly indicated that the effect of glutamine limitation in transformed cells was first to slow down the S phase traverse, then, when a more severe limitation was established, to stuck a large fraction of the cells population in S-phase. Indeed, addition of a mix of 10µM deoxyribonucleotides reverted completely S phase reaching.
Therefore in cells exhibiting high metabolic rates, such as rapidly dividing cancer cells grown in vitro, glutamine, being the most readily available amino acid used as energy source, may became the major source to sustain protein and nucleic acid synthesis (Ziegler et al., 2001), especially when glucose levels are low and energy demand is high. However, analysis of the levels of mRNA, proteins and above all of ATP in normal and transformed cells grown in high and low glutamine availability, did not show particular differences, suggesting an important role of glutamine for nucleotides synthesis in K-ras transformed cells.
In conclusion, glutamine shortage in K-ras transformed cells limits proliferation by inducing abortive S phase entrance, while glucose shortage in the same system enhanced cell death (Lopez-Rios et al., 2007; Mankoff et al., 2007). The differential effects of glutamine and glucose on cell viability are not a property of the transformed phenotype per se, but rather depend on the specific pathway being activated in transformation.
It has been previously shown that nutrient shortage influence cell proliferation and G1/S transition of K-Ras transformed fibroblasts.
To understand how intracellular and extracellular signals are transmitted to the cell-cycle machinery and how the latter adjusts its frequencies accordingly is one of the major challenges in molecular biomedicine. To this aim, a computational model of the cell cycle based on experimental data has been developed. Indeed biochemical and genetic studies can be combined with bioinformatics and biosystems approaches in order to sketch a plan of the regulatory circuits governing cell cycle progression in normal cells, firstly, and then in transformed cells.
Taking in consideration that the trespassing of the Restriction Point influences the timing of the cell cycle execution and that such timing is influenced both by growth factors and nutrients availability, it has been initially identified the restriction point in normal mouse fibroblasts, synchronized in G0 by serum starvation and stimulated to re-enter into S-phase by readdition of serum. During the time course of re-entering into cell cycle, from G0 to G1/S phase, and in agree with restriction point reaching, it has been observed a gradual increase of cyclin D and cyclin E, a constant expression of Cdk4 and Cdk2 and an abrupt decrease of p27Kip1. Moreover, in quiescent cells, has been observed a completely nuclear localization of p27Kip1 and more cytoplasmic localization of Cdk4 and Cdk2. These data agreed with other results since, in most cases, the concentration of the kinase subunit is relatively constant, whereas the concentration of the cyclin subunit oscillates. This detailed study of G1/S transition in normal fibroblasts allowed a novel mathematical model develop. Because tumor cells often display a reduced dependence on growth factors or an increased dependence on some nutrients, an understanding of the cell cycle and a dynamical computational model that include regulatory aspect might help explain the changes leading to tumor formation.
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Toda, Kosuke. "Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225464.
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Maddula, Sasidhar [Verfasser]. "Cell cycle phase specific metabolism of colon cancer cells: a metabolome study / Sasidhar Maddula." München : Verlag Dr. Hut, 2011. http://d-nb.info/1018980911/34.
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Neumann, Chase K. A. "Phosphatidylinositol Remodeling through Membrane Bound O-acyl Transferase Domain-7 (MBOAT7) Promotes the Progression of Clear Cell Renal Cell Carcinoma (ccRCC)." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1586250046745924.
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Yang, Jie. "Prediction of combination efficacy in cancer therapy." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/prediction-of-combination-efficacy-in-cancer-therapy(1b49824b-9d5f-4d21-89d7-6160a810d05e).html.
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The cell cycle is an essential process in all living organisms that must be carefully regulated to ensure successful cell growth and division. Disregulation of the cell cycle is a key contributing factor towards the formation of cancerous cells. Understanding events at a cellular level is the first step towards comprehending how cancer manifests at an organismal level. Mathematical modelling can be used as a means of formalising and predicting the behaviour of the biological systems involved in cancer. In response, cell cycle models have been constructed to simulate and predict what happens to the mammalian cell over a time course in response to variable parameters.Current cell cycle models rarely account for certain precursors of cell growth such as energy usage and the need for non-essential amino acids as fundamental building blocks of macromolecules. Normal and cancer cell metabolism differ in the way they derive energy from glucose. In addition, normal and cancer cells also demonstrate different levels of gene expression. Two versions of a mammalian cell cycle and metabolism model, based on ordinary differential equations (ODEs) that respond to fluctuations in glucose concentration levels, have been developed here for the normal and cancer cell scenarios. Sensitivity analysis is performed for both normal and cancer cells using these cell cycle and metabolism models to investigate which kinetic reaction steps have a greater effect over the cell cycle period. Detailed analysis of the models and quantitatively assessing metabolite levels at various stages of the cell cycle may offer novel insights into how the glycolytic rate varies during the cell cycle for both normal and cancer cells.The results of the sensitivity analysis are used to identify potential drug targets in cancer therapy. Combinations of these individual targets are also investigated to compare the different effects of single and multiple drug compounds on the time it takes to complete a cell division cycle.
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Moulin, Cécile. "Analyse des voies métaboliques au cours du cycle cellulaire : application au métabolisme du cancer." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASG022.
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L’objectif de cette thèse est d’étudier comment la cellule mammifère adapte son métabolisme aux étapes du cycle cellulaire. Le cycle cellulaire est l’ensemble des étapes menant une cellule à se diviser. Le rôle du métabolisme est de fournir à la cellule les éléments et l’énergie dont elle a besoin pour fonctionner. En particulier, à chaque étape du cycle cellulaire, la cellule a besoin de différents éléments pour pouvoir, à terme, se diviser correctement. Il est donc crucial pour la cellule de coordonner le métabolisme et le cycle cellulaire et en particulier de contrôler ce que le métabolisme produit au cours du cycle cellulaire. Pour mieux comprendre ce lien entre ces deux processus, nous avons étudié comment un modèle mathématique du métabolisme répondait à différentes variations imposées par le cycle cellulaire et nous avons comparé ces réponses à la littérature. Satisfaits des résultats obtenus, nous avons alors construit un modèle hybride représentant l’évolution du métabolisme au cours du cycle cellulaire. Nous retrouvons dans ce modèle hybride les grandes variations connues des voies métaboliques au cours des phases du cycle cellulaire ainsi que des variations expérimentales des métabolites énergétiques et redox. Encouragés par ces résultats, nous avons finalement perturbé notre modèle hybride pour retrouver des tendances du métabolisme dues au cancer, un ensemble de maladies touchant à la fois le cycle cellulaire et le métabolismeThe goal of this thesis is to study how the mammal cell adjusts its metabolism to the steps of the cell cycle. The cell cycle is the series of events leading a cell to divide itself. The purpose of the metabolism is to supply the cell with all the elements and the energy it needs to work. In particular, at every step of the cell cycle, the cell needs different elements to properly divide itself. So, it is crucial for the cell to coordinate the metabolism and the cell cycle and in particular to control what the metabolism produces through the cell cycle. To have a better understanding of the links between these two processes, we studied how a mathematical model representing the metabolism answered to different variations imposed by the cell cycle and we compared those answers to the literature. Satisfied by the results, we therefore built a hybrid model representing the evolution of the metabolism through the cell cycle. We recover in this hybrid model the main known variations of the metabolism through the cycle’s phases as well as experimental variations of the energetic and redox metabolites. Encouraged by these results, we finally disturbed our hybrid model to recover metabolic tendencies due to cancer, a set of diseases affecting both the metabolism and the cell cycle
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Silva, Alinne Costa. "Aparato de importação de proteínas mitocondriais em Aspergillus fumigatus: caracterização fenotípica da deleção da menor subunidade do complexo TIM23." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17131/tde-06062017-161751/.
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O câncer de ovário (OvCa) se destaca dentre as neoplasias ginecológicas por ser um dos mais letais e de difícil diagnóstico. O OvCa ocorre devido ao acúmulo de alterações celulares progressivas promovidas por mutações no genoma de uma célula que, consequentemente, alteram as complexas vias de regulação celular que respondem a fatores internos, como reprogramação genética, ou externos, como a resposta a fatores de crescimento, que juntamente com outras alterações moleculares favorecem a progressão e a metástase. Uma importante etapa da cascata metastática é a transição epitélio-mesenquimal (EMT), um processo bem orquestrado que resulta na perda do fenótipo epitelial e aquisição do fenótipo mesenquimal pelas células tumorais, que adquirem um caráter mais invasivo e migratório, além de se tornarem mais resistentes às drogas. A desregulação de fatores de transcrição como ZEB1, TWIST e SNAI1, vias de sinalização, microRNAs e fatores de crescimento incluindo EGF, TGF? e HGF podem desencadear a EMT. Após a eficiente indução da EMT com EGF na linhagem epitelial de adenocarcinoma de ovário humano Caov-3, foi realizada a análise proteômica quantitativa detalhada, baseada na análise de frações subcelulares enriquecidas em proteínas de membrana, citosol e núcleo, obtidas por centrifugação diferencial e subsequente fracionamento de proteínas por SDS-PAGE, a fim de compreender mais profundamente os mecanismos moleculares modulados pela EMT no OvCa. A partir da análise dos dados coletados em um sistema de espectrometria de massas de alta resolução acoplados a cromatografia líquida (LCMS/MS) e com o auxílio da bioinformática foram identificadas redes de interação proteína-proteína diferencialmente expressas, relacionadas principalmente com a regulação do ciclo celular e do metabolismo. A indução da EMT por EGF resultou na ativação de importantes vias de sinalização, tais como PI3K/Akt/mTOR e Ras/MAPK Erk, além da parada do ciclo celular na fase G1 regulada pelo aumento dos níveis de p21Waf1/Cip1, independentemente de p53, e diminuição de proteínas checkpoint. Através da proteômica dirigida, o monitoramento de reações múltiplas (MRM) revelou que, após a indução da EMT por EGF, o metabolismo das células Caov-3 foi alterado de uma maneira bastante peculiar. O estudo proteômico descrito permitiu a correlação entre processo da EMT induzido por EGF com o controle translacional, a regulação do ciclo celular e a alteração do metabolismo energético.Ovarian cancer (OvCa) stands out among gynecological malignancies for being one of the most lethal and difficult to diagnose. OvCa occurs due to the accumulation of progressive cell changes promoted by mutations in the cell genome which, consequently, alter the complex cellular regulation pathways that respond to internal factors, such as genetic reprogramming, or external, such as response to growth factors, which together with other molecular changes favor the progression and metastasis. An important step of the metastatic cascade is the epithelial-mesenchymal transition (EMT), a well-orchestrated process that results in the loss of epithelial phenotype and acquisition of mesenchymal phenotype by tumor cells that acquire a more invasive and migratory character, and become more resistant to drugs. Deregulation of transcription factors such as ZEB1, TWIST and SNAI1, signaling pathways, microRNAs and growth factors including EGF, TGF? and HGF can trigger EMT. After an efficient EMT induction by EGF in the epithelial cell line of human adenocarcinoma ovarian Caov-3, detailed quantitative proteomic analysis was performed based on analysis of subcellular fractions enriched in proteins from membrane, cytosol and nucleus, obtained by differential centrifugation and subsequent fractionation of proteins by SDS-PAGE, in order to understand deeply the molecular mechanisms modulated by EMT in OvCa. From the analysis of data collected in a highresolution mass spectrometry system coupled to liquid chromatography (LC-MS/MS) and with the aid of bioinformatics were identified protein-protein interaction networks differentially expressed, mainly related to regulation cell cycle and metabolism. EGF induced-EMT resulted in the activation of major signaling pathways such as PI3K/Akt/mTOR and Ras/MAPK Erk, in addition to G1 phase cell cycle arrest regulated by increased levels of p21Waf1/Cip1, regardless of p53, and reduction of checkpoint proteins. Through the targeted proteomics, multiple reaction monitoring (MRM) showed that after EGF induced-EMT, Caov-3 cells metabolism was changed in a very particular way. The proteomic study described allowed the correlation between EMT process induced by EGF with translational control, regulation of cell cycle and the change in the energy metabolism.
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Kinkade, Rebecca. "Rb-Raf-1 interaction as a therapeutic target for proliferative disorders." [Tampa, Fla] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002426.
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Nandagopal, Neethi. "Identification of copper metabolism as a KRAS-specific vulnerability in colorectal cancer." Thesis, 2020. http://hdl.handle.net/1866/25272.
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KRAS est parmi les gènes les plus fréquemment mutés dans les cancers humains, tel que ~ 45% des cancers colorectaux (CCR). Malgré les efforts déployés pour réduire son potentiel oncogénique, KRAS muté est fréquemment associé à la résistance aux médicaments et est extrêmement difficile à cibler sur le plan thérapeutique. Les protéines à la surface cellulaire sont souvent dérégulées dans les cancers et sont des cibles thérapeutiques attrayantes en raison de leur accessibilité aux anticorps. Nous avons séquençé les ARNm de cellules épithéliales intestinales exprimant KRAS muté et observé que ces dernières présentaient des changements importants dans les gènes codant pour des protéines de surface cellulaire. Par conséquent, notre objectif était d'identifier de nouvelles cibles thérapeutiques exprimées à la surface de cellules transformées par l’oncogène KRAS. En utilisant une approche de pointe en protéomique de surface cellulaire, nous avons identifié plusieurs protéines différentiellement exprimées dans les cellules avec KRAS muté par rapport à leurs homologues de type sauvage. Nous avons ensuite effectué un crible CRISPR/Cas9 basé sur les protéines de surface cellulaire, qui a révélé que la perte de la protéine Atp7a affectait de manière différentielle les cellules épithéliales intestinales, en fonction de leur statut KRAS. De façon intéressante, nous avons constaté que ATP7A était régulé à la hausse dans les cellules avec KRAS muté par rapport à leurs homologues de type sauvage. ATP7A a un double rôle dans les cellules; alors qu'il est essentiel pour la maturation des enzymes dépendantes du cuivre (Cu), ATP7A protège les cellules d'une toxicité excessive induite par le Cu (cuproptose). Chez l'homme, les mutations dans ATP7A entraînent des troubles caractérisés par des déficiences systémiques dans le transport et les niveaux de Cu. Chez les animaux et dans les modèles de culture cellulaire, tel que les cellules épithéliales intestinales, les niveaux intracellulaires de Cu sont directement corrélés avec l'abondance post-transcriptionnelle d'ATP7A. Dans le même ordre d'idées, nous avons observé que les cellules de CCR avec KRAS muté avaient relativement plus de Cu intracellulaire, et la surexpression d'ATP7A protégeait les cellules KRAS muté de la cuproptose, par rapport à leurs homologues de type sauvage. Nous avons également observé que la croissance in vivo des xénogreffes KRAS mutées était réduite lorsque les souris étaient nourries avec un régime pauvre en Cu. Le Cu est utilisé par plusieurs enzymes qui régulent des fonctions cellulaires critiques, notamment la respiration mitochondriale, la motilité cellulaire et la prolifération. Nous montrons que les cellules mutantes KRAS étaient plus sensibles au chélateur de Cu, ammonium tetrathiomolybdate (TTM), par rapport aux cellules de type sauvage. De plus, les cellules avec KRAS muté traitées avec le TTM ont présenté des activités réduites de MEK1/2 dépendant du Cu et de l'enzyme de la chaîne de transport d'électrons mitochondriale, cytochrome c oxidase (CCO). Nous avons été surpris de constater que le transporteur de Cu de haute affinité, CTR1, est régulé à la baisse dans les cellules avec KRAS muté, et avons donc émis l'hypothèse que les cellules KRAS mutées doivent absorber le Cu par d'autres moyens. Ainsi, nous avons constaté que la macropinocytose agit comme une voie non canonique d'approvisionnement en Cu dans les cellules avec KRAS muté. Le traitement de cellules in vivo avec l'inhibiteur de la macropinocytose, EIPA, a inhibé l'expression d'ATP7A et diminué le Cu biodisponible dans les xénogreffes KRAS mutées. En conclusion, nos résultats montrent que les cellules avec KRAS muté augmentent les niveaux de Cu et d'ATP7A pour soutenir la tumorigenèse en augmentant l'activité cuproenzymatique et diminuant la cuproptose. Cette étude est pertinente pour le cancer, car les tissus tumoraux contiennent fréquemment des niveaux de Cu plus élevés que les tissus normaux. Des études récentes ont mis en évidence un potentiel de repositionnement du chélateur de Cu TTM, qui est disponible en clinique et utilisé pour traiter les troubles du Cu. Nos résultats démontrent que la biodisponibilité du Cu pourrait être exploitée pour traiter le CCR avec KRAS muté avec de tels inhibiteurs. Les travaux futurs comprennent l'identification de stratégies combinatoires qui peuvent être améliorer les effets anti-cancéreux de la chélation du Cu.KRAS is amongst the most frequently mutated genes driving human cancers, including ~ 45% of colorectal cancers (CRC). Despite intense efforts to curb its oncogenic potential, mutant KRAS is frequently associated with drug resistance and is extremely challenging to target therapeutically. Cell-surface proteins are often spatially dysregulated in cancers and are attractive therapeutic targets due to their easy accessibility. We performed RNA sequencing of mutant KRAS-expressing intestinal epithelial cells and observed that cells undergoing transformation exhibited dramatic changes in cell surface-coding genes. Therefore, our goal was to identify novel druggable targets expressed at the cell surface of mutant KRAS-transformed cells. Using a cutting-edge cell surface proteomics approach, we identified several differentially expressed proteins at the surface of KRAS-mutant cells compared to wild-type counterparts. We then performed a cell surface based CRISPR/Cas9 screen, which revealed that loss of the copper exporter Atp7a differentially affected the fitness of intestinal epithelial cells, depending on their KRAS status. Interestingly, we found that ATP7A was upregulated in KRAS-mutant cells compared to wild-type counterparts. ATP7A has a dual role in cells; while it is essential for maturation of copper (Cu)-dependent enzymes, ATP7A protects cells from excess Cu-induced toxicity (cuproptosis). In humans, ATP7A mutations result in disorders characterized by systemic deficiencies in Cu transport and levels. In animals and in tissue culture models, including intestinal epithelial cells, intracellular Cu levels are directly correlated with the post-transcriptional abundance of ATP7A. In line with this, we observed that KRAS-mutant CRC cells and tissues had relatively more intracellular Cu, and ATP7A-overexpression protected KRAS-mutant cells from cuproptosis, compared to wild-type counterparts. We also observed that in vivo growth of KRAS-mutant xenografts was reduced when mice were fed a Cu-deficient diet. Cu is utilized by several enzymes that regulate critical cellular functions including mitochondrial respiration, cell motility and proliferation. We show that KRAS-mutant cells were more sensitive to the Cu chelating drug ammonium tetrathiomolybdate (TTM), compared to wild-type cells. Moreover, TTM-treated KRAS-mutant cells displayed reduced activities of Cu-dependent MEK1/2 and mitochondrial electron transport chain enzyme, cytochrome c oxidase (CCO). We were surprised to find that the high-affinity CTR1 importer is downregulated in KRAS-mutant cells, and so we hypothesized that KRAS cells must uptake Cu through alternate means. In accordance with this, we found that macropinocytosis acts as a non-canonical Cu-supply route in KRAS-mutant cells. In vivo, treating cells with the macropinocytosis inhibitor EIPA, inhibited the expression of ATP7A and decreased bioavailable Cu in KRAS xenografts. In conclusion, our results show that KRAS-mutant cells increase Cu and ATP7A levels, likely to support tumorigenesis by elevating cuproenzymatic activity and parallelly dealing with cuproptosis. This study is relevant to cancer as tumor tissues and patients contain higher Cu levels than normal controls. Recent studies have highlighted a potential for repurposing the clinically available copper chelator TTM, which is used to treat Cu disorders. Our results demonstrate that copper bioavailability could be exploited to treat KRAS-mutated CRC with such inhibitors. Future work includes identification of combinatorial strategies that may be synthetic lethal to copper chelation.
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Przybytkowski, Ewa. "Fatty acid metabolism and modulation of human breast cancer cell survival." Thèse, 2006. http://hdl.handle.net/1866/15602.
Full textBooks on the topic "Metabolism, Cell Cycle, Cancer, Kras"
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Whitfield, James F. Calcium in cell cycles and cancer. 2nd ed. Boca Raton, Fla: CRC Press, 1995.
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Calcium, cell cycles, and cancer. Boca Raton, Fla: CRC Press, 1990.
Find full textBook chapters on the topic "Metabolism, Cell Cycle, Cancer, Kras"
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Çoban, Esra Aydemir, Didem Tecimel, Fikrettin Şahin, and Ayşen Aslı Hızlı Deniz. "Targeting Cancer Metabolism and Cell Cycle by Plant-Derived Compounds." In Advances in Experimental Medicine and Biology, 125–34. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/5584_2019_449.
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Li, Ting, Christopher Copeland, and Anne Le. "Glutamine Metabolism in Cancer." In The Heterogeneity of Cancer Metabolism, 17–38. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-65768-0_2.
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AbstractMetabolism is a fundamental process for all cellular functions. For decades, there has been growing evidence of a relationship between metabolism and malignant cell proliferation. Unlike normal differentiated cells, cancer cells have reprogrammed metabolism in order to fulfill their energy requirements. These cells display crucial modifications in many metabolic pathways, such as glycolysis and glutaminolysis, which include the tricarboxylic acid (TCA) cycle, the electron transport chain (ETC), and the pentose phosphate pathway (PPP) [1]. Since the discovery of the Warburg effect, it has been shown that the metabolism of cancer cells plays a critical role in cancer survival and growth. More recent research suggests that the involvement of glutamine in cancer metabolism is more significant than previously thought. Glutamine, a nonessential amino acid with both amine and amide functional groups, is the most abundant amino acid circulating in the bloodstream [2]. This chapter discusses the characteristic features of glutamine metabolism in cancers and the therapeutic options to target glutamine metabolism for cancer treatment.
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Schulze, Almut, Karim Bensaad, and Adrian L. Harris. "Cancer metabolism." In Oxford Textbook of Cancer Biology, edited by Francesco Pezzella, Mahvash Tavassoli, and David J. Kerr, 221–38. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780198779452.003.0016.
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Abnormalities in cancer metabolism have been noted since Warburg first described the phenomenon of glycolysis in normoxic conditions. This chapter reviews the major pathways in metabolism known to be modified in cancer, including glycolysis and the Krebs cycle, the pentose shunt, and new data implicating the role of different metabolic adaptations, including oncometabolism. It highlights the genetic changes that effect metabolism including many of the commonly occurring oncogenes but also rare mutations that specifically target metabolism. Nutrient and oxygen limitation and proliferation create the microenvironmental selective stress for modifications in hypoxic metabolism, but also affect other cell types such as endothelial cells and macrophages. This range of changes provides many new therapeutic approaches. It also describes the potential value of targeting these adaptations and approaches to monitoring in vivo effects in patients to monitor therapeutic activity.
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"Cell Cycle and Energy Metabolism in Tumor Cells: Strategies for Drug Therapy." In Topics in Anti-Cancer Research, edited by Nivea D. Amoêdo, Tatiana El-Bacha Porto, Mariana F. Rodrigues, and Franklin D. Rumjanek, 197–230. BENTHAM SCIENCE PUBLISHERS, 2013. http://dx.doi.org/10.2174/9781608051366113020008.
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Zhan, Xianquan, and Na Li. "The Anti-Cancer Effects of Anti-Parasite Drug Ivermectin in Ovarian Cancer." In Ovarian Cancer - Updates in Tumour Biology and Therapeutics [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.95556.
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Ivermectin is an old, common, and classic anti-parasite drug, which has been found to have a broad-spectrum anti-cancer effect on multiple human cancers. This chapter will focus on the anti-cancer effects of ivermectin on ovarian cancer. First, ivermectin was found to suppress cell proliferation and growth, block cell cycle progression, and promote cell apoptosis in ovarian cancer. Second, drug pathway network, qRT-PCR, and immunoaffinity blot analyses found that ivermectin acts through molecular networks to target the key molecules in energy metabolism pathways, including PFKP in glycolysis, IDH2 and IDH3B in Kreb’s cycle, ND2, ND5, CYTB, and UQCRH in oxidative phosphorylation, and MCT1 and MCT4 in lactate shuttle, to inhibit ovarian cancer growth. Third, the integrative analysis of TCGA transcriptomics and mitochondrial proteomics in ovarian cancer revealed that 16 survival-related lncRNAs were mediated by ivermectin, SILAC quantitative proteomics analysis revealed that ivermectin extensively inhibited the expressions of RNA-binding protein EIF4A3 and 116 EIF4A3-interacted genes including those key molecules in energy metabolism pathways, and also those lncRNAs regulated EIF4A3-mRNA axes. Thus, ivermectin mediated lncRNA-EIF4A3-mRNA axes in ovarian cancer to exert its anticancer capability. Further, lasso regression identified the prognostic model of ivermectin-related three-lncRNA signature (ZNRF3-AS1, SOS1-IT1, and LINC00565), which is significantly associated with overall survival and clinicopathologic characteristics in ovarian cancer patients. These ivermectin-related molecular pattern alterations benefit for prognostic assessment and personalized drug therapy toward 3P medicine practice in ovarian cancer.
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Gomes Morais, Mariana, Francisca Guilherme Carvalho Dias, João Alexandre Velho Prior, Ana Luísa Pereira Teixeira, and Rui Manuel de Medeiros Melo Silva. "The Impact of Oxidoreductases-Related MicroRNAs in Glucose Metabolism of Renal Cell Carcinoma and Prostate Cancer." In Oxidoreductase. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.93932.
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The reprogramming of metabolism is one of cancer hallmarks. Glucose’s metabolism, as one of the main fuels of cancer cells, has been the focus of several research studies in the oncology field. However, because cancer is a heterogeneous disease, the disruptions in glucose metabolism are highly variable depending of the cancer. In fact, Renal Cell Carcinoma (RCC) and Prostate Cancer (PCa), the most lethal and common urological neoplasia, respectively, show different disruptions in the main pathways of glucose catabolism: glycolysis, lactate fermentation and Krebs Cycle. Oxidoreductases are a class of enzymes that catalyze electrons transfer from one molecule to another and are present in these three pathways, posing as an opportunity to better understand these catabolic deregulations. Furthermore, nowadays it is recognized that their expression is modulated by microRNAs (miRNAs), in this book chapter, we selected the known miRNAs that directly target these oxidoreductases and analyzed their deregulation in both cancers. The characterization of these miRNAs opens a new door that could be applied in patients’ stratification and therapy monitorization because of their potential as cancer biomarkers. Additionally, their delivery to cancer cells, using glucose capped NPs could help establish new therapeutic strategies that would improve RCC and PCa management.
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Xu, Jingwen, and Weiqun Wang. "Fiber-associated wheat lignans and colorectal cancer prevention." In Improving the nutritional and nutraceutical properties of wheat and other cereals, 115–36. Burleigh Dodds Science Publishing, 2021. http://dx.doi.org/10.19103/as.2021.0087.10.
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Wheat, as a staple food, has been largely consumed worldwide. In addition to nutritional values, whole grain including fiber-enriched wheat bran has been reported to provide many nutraceuticals such as wheat lignans. This chapter reviews recent epidemiological and animal data on wheat lignans and their role in colorectal cancer prevention. It covers aspects of the lignan structure, biosynthesis, analysis, metabolism and potential health benefits with emphasis on anti-proliferative, anti-oxidant, anti-inflammation, anti-estrogenic and cell cycle arrest mechanisms. Human epidemiological studies suggest dietary intake of lignans is associated with reducing risk of many chronic diseases such as cardiovascular disease, chronic bowel inflammation, and certain types of cancer including colorectal cancer. The bioactivity of wheat lignans has been shown to be influenced by their chemical forms and microbial flora-induced metabolites. Compelling animal study data suggest that dietary lignans or wheat lignans contribute to colorectal cancer prevention; however, further clinical intervention studies appear warranted.
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Wang, Jin, Qifei Wang, and Guangzhen Wu. "An Important Component of Tumor Progression: Fatty Acids." In Fatty Acids - Recent Advances [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.105087.
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Fatty acids (FAs) are complex and essential biomolecules in the human body and are critical to the formation of cell membranes, energy metabolism, and signaling. FAs are the major components of several lipids including phospholipids, sphingolipids, and triglycerides, and consist of carboxylic acid groups and hydrocarbon chains of different carbon lengths and degrees of desaturation. They can synthesize more complex lipids, including acylglycerides (DAG) and triacylglycerides (TAG). Saturated fatty acids (SFA), polyunsaturated fatty acids (PUFA), and monounsaturated fatty acids (MUFA) can be classified according to whether the hydrocarbon chain is saturated or not. Normal cells are commonly supplied with energy by the tricarboxylic acid cycle. On the contrary, to obtain energy, tumor cells usually use aerobic glycolysis (Warburg effect) and produce large amounts of FAs to maintain membrane structure to support cell proliferation. In addition, cancer migration, immune escape, development of drug resistance, and fatty acids are very closely related. In conclusion, a deeper understanding of the molecular mechanisms of fatty acid metabolism could provide a more plausible explanation for the progression of cancer cells and provide new potential targets for therapy.
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Grossman, Moran, and Elaine Adler. "Protein Kinase Inhibitors - Selectivity or Toxicity?" In Protein Kinase - New Opportunities, Challenges and Future Perspectives [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.98640.
Full textAbstract:
Protein kinases are attractive therapeutic targets for various indications including cancer, cardiovascular, neurodegenerative and autoimmune diseases. This is due to the fact that they play key roles in the regulation of cell cycle, metabolism, cell adhesion, angiogenesis, regeneration and degeneration. Protein kinase families share a common catalytic core and hence usually display clear sequence and structural similarity. These sequence and structural similarities can lead to a lack of selectivity and off-target toxicity of drug candidates. The lack of selectivity can be beneficial but can also cause adverse toxicities which result in the discontinuation of promising drug candidates. The chapter reviews the challenges and common toxicities of protein kinase inhibitors and the latest advances in in-vitro and in-silico assays to screen for selectivity. The various methods for quantifying selectivity of kinase inhibitors and future directions including emerging more selective and safer kinase inhibitors have also been discussed.
Conference papers on the topic "Metabolism, Cell Cycle, Cancer, Kras"
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Salvucci, Manuela, Robert O’Byrne, Natalia Niewidok, Séan Kilbride, Caoimhín G. Concannon, Heiko Düssmann, Heinrich H. Huber, and Jochen HM Prehn. "Abstract 1012: Systems analysis of colon cancer cell metabolism rewired by p53 and KRAS mutations." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-1012.
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Rozeveld, Cody, Ryan Schulze, Lizhi Zhang, and Gina L. Razidlo. "Abstract PR09: KRas modulates pancreatic cancer cell metabolism and invasive potential through the lipase HSL." In Abstracts: AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; September 6-9, 2019; Boston, MA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.panca19-pr09.
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Gwinn, Dana M., and Alejandro Sweet-Cordero. "Abstract B27: Kras alters expression of asparagine synthetase (Asns) in non-small cell lung cancer (NSCLC) and protects tumors during nutrient stress." In Abstracts: AACR Special Conference: Metabolism and Cancer; June 7-10, 2015; Bellevue, WA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1557-3125.metca15-b27.
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Andrew, Angeline S., Jiang Gui, Jason H. Moore, Margaret R. Karagas, Eben Pendleton, Alan R. Schned, Rebecca A. Mason, et al. "Abstract A66: Apoptosis, cell cycle, DNA repair, immune, and metabolism pathway SNPs modify bladder cancer risk, recurrence, and survival." In Abstracts: AACR International Conference on Frontiers in Cancer Prevention Research‐‐ Oct 22-25, 2011; Boston, MA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1940-6207.prev-11-a66.
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Gut, Ivan, Marie Ehrlichova, Radka Vaclavikova, Iwao Ojima, and Petr Simek. "Abstract A147: Novel fluorinated taxane SB‐T‐12854 active in drug‐resistant and sensitive cell lines: Human, pig, rat metabolism, cell transport, and effects on cell cycle." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-a147.
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Váraljai, Renáta, Abul B. M. M. K. Islam, Nicholas J. Dyson, and Elizaveta V. Benevolenskaya. "Abstract B01: pRb activates mitochondrial metabolism and promotes differentiation through the histone demethylase Kdm5a." In Abstracts: AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; February 28 - March 2, 2016; Orlando, FL. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1557-3125.cellcycle16-b01.
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