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1
López, Esther, Alejandro Berna-Erro, Javier J. López, María P. Granados, Nuria Bermejo, José M. Brull, Ginés M. Salido, Juan A. Rosado, and Pedro C. Redondo. "Role of mTOR1 and mTOR2 complexes in MEG-01 cell physiology." Thrombosis and Haemostasis 114, no. 11 (2015): 969–81. http://dx.doi.org/10.1160/th14-09-0727.
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SummaryThe function of the mammalian target of rapamycin (mTOR) is upregulated in response to cell stimulation with growing and differentiating factors. Active mTOR controls cell proliferation, differentiation and death. Since mTOR associates with different proteins to form two functional macromolecular complexes, we aimed to investigate the role of the mTORI and mTOR2 complexes in MEG-01 cell physiology in response to thrombopoietin (TPO). By using mTOR antagonists and overexpressing FKBP38, we have explored the role of both mTOR complexes in proliferation, apoptosis, maturation-like mechanisms, endoplasmic reticulum-stress and the intracellular location of both active mTOR complexes during MEG-01 cell stimulation with TPO. The results demonstrate that mTOR1 and mTOR2 complexes play different roles in the physiology of MEG-01 cells and in the maturation-like mechanisms; hence, these findings might help to understand the mechanism underlying generation of platelets.
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Białoń, Natalia, Krzysztof Suszyński, Mikołaj Górka, Michał Trzęsicki, Dariusz Górka, Kacper Zając, and Agata Kupczak. "Szlak mTOR i zwierzęta transgeniczne z delecją genu TSC w procesie regeneracji układu nerwowego i wybranych modelach uszkodzeń nerwu kulszowego." Postępy Biochemii 69, no. 3 (September 3, 2023): 159–69. http://dx.doi.org/10.18388/pb.2021_489.
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Urazowe uszkodzenia układu nerwowego od lat są powszechnym zjawiskiem, które obniżają jakość życia pacjentów. Szlak mTOR (ang. mammalian target of rapamycin) pełni kluczową rolę w fizjologii układu nerwowego, między innymi poprzez kontrolę przeżywania i różnicowania komórek nerwowych. Nadmierna aktywacja szlaku mTOR prowadzi do wzrostu aktywności białek cyklu komórkowego i apoptozy komórek nerwowych. Ponadto, aktualne odkrycia sugerują udział szlaku mTOR w neuroplastyczności. Wykorzystanie zwierząt transgenicznych z delecją genu TSC jak i różnych modeli uszkodzeń nerwu kulszowego, pozwala na aktywację szlaku mTOR. Obecnie wyniki badań potwierdzają, iż inaktywacja mutacji punktowych w genach TSC-1 lub TSC-2 aktywuje kanoniczną ścieżkę sygnałową kompleksu mTORC-1, z kolei reaktywacja szlaku mTORC-1 poprzez absencję genu TSC-1 w dojrzałych neuronach indukuje regenerację aksonów. Zaburzenia funkcji szlaku mTORC-1 w komórkach Schwanna hamują mielinizację włókien nerwowych. Celem niniejszej pracy jest usystematyzowanie wiedzy i przedstawienie roli szlaku mTOR, jak również wykazanie roli delecji genu TSC w procesie regeneracji układu nerwowego. Obecne badania nad aktywnością szlaku mTOR mogą zapewnić nowe strategie intensyfikowania regeneracji nerwów obwodowych.
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Wang, Xueyu, Zhiqiang Wei, Yongfang Jiang, Zhongji Meng, and Mengji Lu. "mTOR Signaling: The Interface Linking Cellular Metabolism and Hepatitis B Virus Replication." Virologica Sinica 36, no. 6 (September 28, 2021): 1303–14. http://dx.doi.org/10.1007/s12250-021-00450-3.
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AbstractMammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that includes mTOR complex (mTORC) 1 and mTORC2. The mTOR pathway is activated in viral hepatitis, including hepatitis B virus (HBV) infection-induced hepatitis. Currently, chronic HBV infection remains one of the most serious public health issues worldwide. The unavailability of effective therapeutic strategies for HBV suggests that clarification of the pathogenesis of HBV infection is urgently required. Increasing evidence has shown that HBV infection can activate the mTOR pathway, indicating that HBV utilizes or hijacks the mTOR pathway to benefit its own replication. Therefore, the mTOR signaling pathway might be a crucial target for controlling HBV infection. Here, we summarize and discuss the latest findings from model biology research regarding the interaction between the mTOR signaling pathway and HBV replication.
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Felkai, Luca, Ildikó Krencz, Dorottya Judit Kiss, Noémi Nagy, Gábor Petővári, Titanilla Dankó, Tamás Micsík, et al. "Characterization of mTOR Activity and Metabolic Profile in Pediatric Rhabdomyosarcoma." Cancers 12, no. 7 (July 17, 2020): 1947. http://dx.doi.org/10.3390/cancers12071947.
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mTOR activation has been observed in rhabdomyosarcoma (RMS); however, mTOR complex (mTORC) 1 inhibition has had limited success thus far. mTOR activation alters the metabolic pathways, which is linked to survival and metastasis. These pathways have not been thoroughly analyzed in RMSs. We performed immunohistochemistry on 65 samples to analyze the expression of mTOR complexes (pmTOR, pS6, Rictor), and several metabolic enzymes (phosphofructokinase, lactate dehydrogenase-A, β-F1-ATPase, glucose-6-phosphate dehydrogenase, glutaminase). RICTOR amplification, as a potential mechanism of Rictor overexpression, was analyzed by FISH and digital droplet PCR. In total, 64% of the studied primary samples showed mTOR activity with an mTORC2 dominance (82%). Chemotherapy did not cause any relevant change in mTOR activity. Elevated mTOR activity was associated with a worse prognosis in relapsed cases. RICTOR amplification was not confirmed in any of the cases. Our findings suggest the importance of the Warburg effect and the pentose-phosphate pathway beside a glutamine demand in RMS cells. The expression pattern of the studied mTOR markers can explain the inefficacy of mTORC1 inhibitor therapy. Therefore, we suggest performing a detailed investigation of the mTOR profile before administering mTORC1 inhibitor therapy. Furthermore, our findings highlight that targeting the metabolic plasticity could be an alternative therapeutic approach.
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Saran, Uttara, Michelangelo Foti, and Jean-François Dufour. "Cellular and molecular effects of the mTOR inhibitor everolimus." Clinical Science 129, no. 10 (September 1, 2015): 895–914. http://dx.doi.org/10.1042/cs20150149.
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mTOR (mechanistic target of rapamycin) functions as the central regulator for cell proliferation, growth and survival. Up-regulation of proteins regulating mTOR, as well as its downstream targets, has been reported in various cancers. This has promoted the development of anti-cancer therapies targeting mTOR, namely fungal macrolide rapamycin, a naturally occurring mTOR inhibitor, and its analogues (rapalogues). One such rapalogue, everolimus, has been approved in the clinical treatment of renal and breast cancers. Although results have demonstrated that these mTOR inhibitors are effective in attenuating cell growth of cancer cells under in vitro and in vivo conditions, subsequent sporadic response to rapalogues therapy in clinical trials has promoted researchers to look further into the complex understanding of the dynamics of mTOR regulation in the tumour environment. Limitations of these rapalogues include the sensitivity of tumour subsets to mTOR inhibition. Additionally, it is well known that rapamycin and its rapalogues mediate their effects by inhibiting mTORC (mTOR complex) 1, with limited or no effect on mTORC2 activity. The present review summarizes the pre-clinical, clinical and recent discoveries, with emphasis on the cellular and molecular effects of everolimus in cancer therapy.
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Huo, Yilin, Valentina Iadevaia, and Christopher G. Proud. "Differing effects of rapamycin and mTOR kinase inhibitors on protein synthesis." Biochemical Society Transactions 39, no. 2 (March 22, 2011): 446–50. http://dx.doi.org/10.1042/bst0390446.
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mTOR (mammalian target of rapamycin) forms two distinct types of complex, mTORC (mTOR complex) 1 and 2. Rapamycin inhibits some of the functions of mTORC1, whereas newly developed mTOR kinase inhibitors interfere with the actions of both types of complex. We have explored the effects of rapamycin and mTOR kinase inhibitors on general protein synthesis and, using a new stable isotope-labelling method, the synthesis of specific proteins. In HeLa cells, rapamycin only had a modest effect on total protein synthesis, whereas mTOR kinase inhibitors decreased protein synthesis by approx. 30%. This does not seem to be due to the ability of mTOR kinase inhibitors to block the binding of eIFs (eukaryotic initiation factors) eIF4G and eIF4E. Analysis of the effects of the inhibitors on the synthesis of specific proteins showed a spectrum of behaviours. As expected, synthesis of proteins encoded by mRNAs that contain a 5′-TOP (5′-terminal oligopyrimidine tract) was impaired by rapamycin, but more strongly by mTOR kinase inhibition. Several proteins not known to be encoded by 5′-TOP mRNAs also showed similar behaviour. Synthesis of proteins encoded by ‘non-TOP’ mRNAs was less inhibited by mTOR kinase inhibitors and especially by rapamycin. The implications of our findings are discussed.
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Todeschini, Letizia, Luca Cristin, Alessandro Martinino, Amelia Mattia, Salvatore Agnes, and Francesco Giovinazzo. "The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma." Current Oncology 30, no. 6 (June 9, 2023): 5574–92. http://dx.doi.org/10.3390/curroncol30060421.
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Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.
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Rivas, Donato A., Ben B. Yaspelkis, John A. Hawley, and Sarah J. Lessard. "Lipid-induced mTOR activation in rat skeletal muscle reversed by exercise and 5′-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside." Journal of Endocrinology 202, no. 3 (July 2, 2009): 441–51. http://dx.doi.org/10.1677/joe-09-0202.
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The serine/threonine protein kinase, mammalian target of rapamycin (mTOR) is regulated by insulin and nutrient availability and has been proposed to play a central role as a nutrient sensor in skeletal muscle. mTOR associates with its binding partners, raptor and rictor, to form two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) respectively. We have investigated the assembly of mTORC1/2 and the activation of their downstream substrates (i.e. Akt, S6K1) in response to known effectors of mTOR, excess lipid availability and AMP-activated protein kinase (AMPK) activation/exercise training in rat skeletal muscle. The in vivo formation of mTORC1 and 2 and the activation of their respective downstream substrates were increased in response to chronic (8 weeks) consumption of a high-fat diet. Diet-induced mTORC activation and skeletal muscle insulin resistance were reversed by 4 weeks of exercise training, which was associated with enhanced muscle AMPK activation. In order to determine whether AMPK activation reverses lipid-induced mTOR activation, L6 myotubes were exposed to 0.4 mM palmitate to activate mTORC1/2 in the absence or presence of 5′-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR). Palmitate exposure (4 h) increased insulin-stimulated S6K1 Thr389 phosphorylation by 60%, indicating activation of mTORC1. AMPK activation with 1 mM AICAR abolished lipid-induced mTOR activation in vitro. Our data implicates reductions in mTOR complex activation with the reversal of lipid-induced skeletal muscle insulin resistance in response to exercise training or AICAR and identifies mTOR as a potential target for the treatment of insulin resistance.
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Rosborough, Brian, Dàlia Raïch-Regué, Benjamin Matta, Keunwook Lee, Mark Boothby, Heth Turnquist, and Angus Thomson. "Rapamycin-resistant mTORC1 restrains dendritic cell B7-H1 expression that requires IL-1β to enhance regulatory T cell induction (P1349)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 63.27. http://dx.doi.org/10.4049/jimmunol.190.supp.63.27.
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Abstract Introduction: The mammalian Target of Rapamycin (mTOR) is a central regulator of dendritic cell (DC) function that performs the catalytic activity of mTOR complex (mTORC)1 and 2. mTORC2 functions independently from mTORC1 and is resistant to inhibition by rapamycin (RAPA); however, mTORC1 has both RAPA-sensitive and -resistant outputs. Our goal was to ascertain the role of RAPA-resistant mTOR in DC. Methods: WT C57BL/6 or B7-H1-/- bone marrow-derived DC were generated with the addition of RAPA or ATP-competitive mTOR inhibitor, which blocks all mTOR signaling. DC lacking rictor, an mTORC2-specific subunit, were generated from conditional rictor KO mice. DC induction of regulatory T cells (Treg) was determined in MLR, using BALB/c CD4+CD25- T cell responders. Results and Conclusion: RAPA and mTORC2 deletion reduced DC B7-H1 expression, but ATP-competitive mTOR inhibitors enhanced B7-H1 expression. Augmented B7-H1 expression was blocked by STAT3 inhibition and correlated with reduced expression of the STAT3 negative regulator, SOCS3. DC exposed to ATP-competitive mTOR inhibitors increased Treg induction, which was dependent on DC B7-H1. IL-1β neutralization additionally reduced Treg induction by B7-H1-/- ATP-competitive mTOR inhibitor-exposed DC, suggesting that IL-1β and B7-H1 act additively to promote Treg induction by these DC. These findings establish a RAPA-resistant mTORC1 pathway that acts through SOCS3 and STAT3 to regulate DC B7-H1 expression and Treg induction.
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Chen, Yu-Li, Han-Wei Lin, Nai-Yun Sun, Jr-Chi Yie, Hsueh-Chih Hung, Chi-An Chen, Wei-Zen Sun, and Wen-Fang Cheng. "mTOR Inhibitors Can Enhance the Anti-Tumor Effects of DNA Vaccines through Modulating Dendritic Cell Function in the Tumor Microenvironment." Cancers 11, no. 5 (May 2, 2019): 617. http://dx.doi.org/10.3390/cancers11050617.
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The life span of dendritic cells (DCs) can become short following induced activation, which is associated with metabolic transition due to the regulation of mechanistic target of rapamycin (mTOR). The purpose of this study was to investigate the potential of inhibiting mTOR to modulate DC functions for elevating the anti-tumor effects of DNA vaccines. Therefore, the influences of various inhibitors of mTOR (mTORi) on the expressions of DC maturation markers, the abilities of antigen presenting and processing of BMM-derived DCs and the tumor killing effects of E7-specific CD8+ T lymphocytes activated by BMM-derived DCs were in vitro examined. The anti-tumor effects of connective tissue growth factor (CTGF)/E7 DNA vaccine and/or mTORi were also in vivo analyzed. In our study, suppressive effects of mTORi on the DC maturation markers expressed on BMMCs could be reversed. The mTORi-treated mature BMM-derived DCs tended to be non-apoptotic. These mTORi-treated BMM-derived DCs could have better antigen presenting and processing abilities. The E7-specific cytotoxic CD8+ T lymphocytes could have more potent tumoricidal activity following activation of mTORi-treated BMM-derived DCs. For tumor-bearing mice, those treated with CTGF/E7 DNA vaccine and mTORi indeed can have higher percentages of mature DCs in the TME, better disease control and longer survivals. Consequently, application of mTORi can be a pharmacological approach for temporally increasing life span, antigen presenting and antigen processing of DCs to strengthen the therapeutic outcome of cancer immunotherapy.
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Marin, Philippe, Julie Meffre, and Joël Bockaert. "mTOR." médecine/sciences 29, no. 1 (January 2013): 28–30. http://dx.doi.org/10.1051/medsci/2013291009.
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Lin, Qingxiang (Nick). "Abstract B084: Overcoming drug resistance of ‘tri-complex’ pan-RAS inhibitors: Inhibition of mTOR signaling." Cancer Research 84, no. 2_Supplement (January 16, 2024): B084. http://dx.doi.org/10.1158/1538-7445.panca2023-b084.
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Abstract Background: RAS mutations occur in ~20% of all cancers that drive tumor progression, and therapy targeting most predominant RAS mutations remains unavailable. Mutant-selective RAS inhibitors (RASi), such as FDA-approved KRAS G12C inhibitors, have demonstrated initial clinical responses but drug resistance frequently emerges that minimize the drug efficacy, mechanistically mediated by RAS signaling reactivation. Methods and Results: To address this challenge, we characterized a class of novel pan-RASi that universally inhibit all RAS mutations, which forms a ‘tri-complex’ with the chaperone protein (cyclophilin A) that specifically binds to RAS, including wild-type RAS (KRAS, NRAS, HRAS). Mutant-selective RASi induced RAS signaling rebound intensively, whereas pan-RASi enabling to inhibit wild-type RAS minimized this rebound, which was surmountable in a concentration-dependent manner. Importantly, pan-RASi abrogated cell viability in patient-derived KRAS-mutant cancer organoids rather than in normal patient-derived wild-type RAS organoids, implicating drug selectivity and manageable toxicity. Interestingly, intrinsic resistance to pan-RASi was rare in RAS-mutant cancer cell screening but was observed only in a handful of pancreatic and lung cancer cell lines. Our time-resolved signaling analyses of pan-RASi treatment showed the re-activation of mTOR signaling and a contrast correlation that mTOR signaling decreased in sensitive lines but remained in resistant lines, underscoring the critical contribution of mTOR pathways to RASi resistance. Mechanistically, we further identified mTOR signaling that drives intrinsic resistance to pan-RASi, and combined pan-RASi with mTOR inhibitors (mTORi) suppressed mTOR signaling in resistant lines, thereby improving efficacy. Conclusion: Pan-RASi hold promise in treating RAS-mutant cancer clinically and a combination of pan-RASi with mTORi can improve drug efficacy. Citation Format: Qingxiang (Nick) Lin. Overcoming drug resistance of ‘tri-complex’ pan-RAS inhibitors: Inhibition of mTOR signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B084.
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King, Renee, Jessica Hill, Bibek Saha, Yuzhen Tong, Brenda Strutt, Mark Russell, Noel Morgan, Sarah Richardson, and David Hill. "Offspring of Mice Exposed to a Low-Protein Diet in Utero Demonstrate Changes in mTOR Signaling in Pancreatic Islets of Langerhans, Associated with Altered Glucagon and Insulin Expression and a Lower β-Cell Mass." Nutrients 11, no. 3 (March 12, 2019): 605. http://dx.doi.org/10.3390/nu11030605.
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Low birth weight is a risk factor for gestational and type 2 diabetes (T2D). Since mammalian target of rapamycin (mTOR) controls pancreatic β-cell mass and hormone release, we hypothesized that nutritional insult in utero might permanently alter mTOR signaling. Mice were fed a low-protein (LP, 8%) or control (C, 20%) diet throughout pregnancy, and offspring examined until 130 days age. Mice receiving LP were born 12% smaller and β-cell mass was significantly reduced throughout life. Islet mTOR levels were lower in LP-exposed mice and localized predominantly to α-rather than β-cells. Incubation of isolated mouse islets with rapamycin significantly reduced cell proliferation while increasing apoptosis. mRNA levels for mTORC complex genes mTOR, Rictor and Raptor were elevated at 7 days in LP mice, as were the mTOR and Raptor proteins. Proglucagon gene expression was similarly increased, but not insulin or the immune/metabolic defense protein STING. In human and mouse pancreas STING was strongly associated with islet β-cells. Results support long-term changes in islet mTOR signaling in response to nutritional insult in utero, with altered expression of glucagon and insulin and a reduced β-cell mass. This may contribute to an increased risk of gestational or type 2 diabetes.
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Avniel-Polak, Shani, Gil Leibowitz, Victoria Doviner, David J. Gross, and Simona Grozinsky-Glasberg. "Combining chloroquine with RAD001 inhibits tumor growth in a NEN mouse model." Endocrine-Related Cancer 25, no. 6 (June 2018): 677–86. http://dx.doi.org/10.1530/erc-18-0121.
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Patients with neuroendocrine neoplasms (NENs) often require systemic treatment, which is frequently limited by the emergence of drug resistance. mTOR inhibitors (mTORi), such as RAD001 (everolimus), have been shown to inhibit neoplasm progression. mTORi stimulates autophagy, a degradation pathway that might promote the survival of neoplasm cells that are exposed to anti-cancer therapy. Chloroquine (CQ), a well-known anti-malarial and anti-rheumatic drug, suppresses autophagy. Based on our previous results, we hypothesized that CQ may enhance the anti-tumorigenic effects of mTORi by inhibiting autophagy and we aimed to examine the anti-tumorigenic effect of CQ, alone or in combination with RAD001. We established a NEN subcutaneous xenograft mouse model and evaluated the effect of the drugs on tumor growth, mTOR pathway, autophagy and apoptosis. CQ alone and in combination with RAD001 significantly decreased neoplasm volume. Histopathological analysis revealed that the combination of CQ and RAD001 markedly inhibited mTOR activity and neoplasm cell growth, along with accumulation of autophagosomes and increased apoptosis. In conclusion, CQ enhances the anti-tumorigenic effect of RAD001 in vivo by inhibiting autophagy. Clinical trials addressing the effects of CQ therapy on neoplasm progression in patients with NENs, mainly in those treated with mTORi, are warranted.
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Koshizuka, Keiichi, Xingyu Wu, Kuniaki Sato, Pham Thuy Vo, Gosia M. Murawska, Tomohiko Ishikawa, Zhiyong Wang, et al. "Abstract 5996: Genome-wide CRISPR screening reveals a central role for ferroptotic cell death in the anti-tumor response to mTOR inhibitors in HNSCC." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5996. http://dx.doi.org/10.1158/1538-7445.am2024-5996.
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Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally, resulting in more than 300,000 deaths each year worldwide. Treatment options for HNSCC patients include surgery, radiation, chemotherapy and molecularly targeted therapies, and although immunotherapies have recently revolutionized the treatment landscape, <20% of HNSCC patients respond to immune check point blockade (ICB) therapies. The survival rate of HNSCC patients has changed only modestly over the past decades, and therefore HNSCC is a significant global health problem with high mortality and morbidity. Genomic alterations converging in the persistent activation of the PI3K/mTOR pathway (>80% cases) represent one of the most frequently altered signaling circuitries in HNSCC. This overreliance on PI3K/mTOR signaling for tumor growth may expose a cancer vulnerability that can be exploited therapeutically, as revealed in recent clinical trials using mTOR inhibitors (mTORi) in HNSCC in the adjuvant and neoadjuvant setting. Here, we took advantage of a whole-genome CRISPR screening approach to identify mechanisms of sensitivity and resistance to mTORi, aimed at increasing their clinical activity. We found that the activation of autophagy, a biological process that plays a paradoxical pro-survival or antitumoral role in a cancer specific fashion, is strictly required for mTORi cell growth inhibition in HNSCC. In depth analysis of our CRISPR screening also revealed multiple hits suggestive of a novel role for iron metabolism and ferroptosis downstream from mTORi. Ferroptosis is iron-dependent regulated cell death process caused by the peroxidation of polyunsaturated fatty acids. Indeed, we found that mTORi induces ferroptosis in HNSCC cells, and that inhibition of ferroptosis reduces the effect of mTORi. Evidence will be presented supporting a novel mechanism linking mTORi-triggered autophagy and the activation of ferroptotic death programs, as well as new synergistic combinations with mTORi by repurposing approved drugs that disable cellular ferroptotic defense mechanisms. Our studies uncovered how mTORi act in HNSCC, thereby revealing new multimodal precision therapies for HNSCC and many human malignancies displaying overactive PI3K/mTOR signaling. Citation Format: Keiichi Koshizuka, Xingyu Wu, Kuniaki Sato, Pham Thuy Vo, Gosia M. Murawska, Tomohiko Ishikawa, Zhiyong Wang, Alfredo A. Molinolo, Edward A. Dennis, Prashant Mali, J. Silvio Gutkind. Genome-wide CRISPR screening reveals a central role for ferroptotic cell death in the anti-tumor response to mTOR inhibitors in HNSCC [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 5996.
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Ruan, Chun, Xinxing Ouyang, Hongzhi Liu, Song Li, Jingsi Jin, Weiyi Tang, Yu Xia, and Bing Su. "Sin1-mediated mTOR signaling in cell growth, metabolism and immune response." National Science Review 6, no. 6 (November 1, 2019): 1149–62. http://dx.doi.org/10.1093/nsr/nwz171.
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Abstract The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase with essential cellular function via processing various extracellular and intracellular inputs. Two distinct multi-protein mTOR complexes (mTORC), mTORC1 and mTORC2, have been identified and well characterized in eukaryotic cells from yeast to human. Sin1, which stands for Sty1/Spc1-interacting protein1, also known as mitogen-activated protein kinase (MAPK) associated protein (MAPKAP)1, is an evolutionarily conserved adaptor protein. Mammalian Sin1 interacts with many cellular proteins, but it has been widely studied as an essential component of mTORC2, and it is crucial not only for the assembly of mTORC2 but also for the regulation of its substrate specificity. In this review, we summarize our current knowledge of the structure and functions of Sin1, focusing specifically on its protein interaction network and its roles in the mTOR pathway that could account for various cellular functions of mTOR in growth, metabolism, immunity and cancer.
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Kilic, Banu, Meryem Temiz-Resitoglu, and Seyhan Sahan Firat. "Targeting mTOR: up-to-date mTOR inhibitors." Biorganic and Medicinal Chemistry Reports 2, no. 1-2 (December 26, 2019): 1–14. http://dx.doi.org/10.25135/bmcr.16.19.09.1417.
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Ito, Daisuke, and Atsushi Kumanogoh. "mTOR Complex Signaling through the SEMA4A–Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 199.4. http://dx.doi.org/10.4049/jimmunol.196.supp.199.4.
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Abstract Mammalian target of rapamycin (mTOR) plays crucial roles in activation and differentiation of diverse types of immune cells. Although several lines of evidence have demonstrated the importance of mTOR-mediated signals in CD4+ T cell responses, the involvement of mTOR in CD8+ T cell responses is not fully understood. In this study, we show that a class IV semaphorin, SEMA4A, regulates CD8+ T cell activation and differentiation through activation of mTOR complex (mTORC) 1. SEMA4A−/− CD8+ T cells exhibited impairments in production of IFN-γ and TNF-α and induction of the effector molecules granzyme B, perforin, and FAS-L. Upon infection with OVA-expressing Listeria monocytogenes, pathogen-specific effector CD8+ T cell responses were significantly impaired in SEMA4A−/− mice. Furthermore, SEMA4A−/− CD8+ T cells exhibited reduced mTORC1 activity and elevated mTORC2 activity, suggesting that SEMA4A is required for optimal activation of mTORC1 in CD8+ T cells. IFN-γ production and mTORC1 activity in SEMA4A−/− CD8+ T cells were restored by administration of recombinant Sema4A protein. In addition, we show that plexin B2 is a functional receptor of SEMA4A in CD8+ T cells. Collectively, these results not only demonstrate the role of SEMA4A in CD8+ T cells, but also reveal a novel link between a semaphorin and mTOR signaling.
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Parkman, Gennie L., Tursun Turapov, David Kircher, William Burnett, Christopher Stehn, Kayla O'Toole, Katie Culver, et al. "Abstract 427: Newer generation mTOR inhibition represents effective therapeutic strategy for BRAF-mutant melanoma." Cancer Research 83, no. 7_Supplement (April 4, 2023): 427. http://dx.doi.org/10.1158/1538-7445.am2023-427.
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Abstract Despite the advent of novel therapies, the five year survival rate for Stage IV melanoma remains at only 30%. This highlights the critical need for new therapeutics to treat this refractory disease. Aberrant activation of the PI3K-AKT pathway is common in melanoma, but efforts to drug this pathway have proven largely ineffective in clinical trials. In our study, we observed that pharmacological inhibition of AKT was ineffective whereas genetic silencing of all three AKT paralogs significantly abrogated melanoma cell growth and led to apoptosis through effects on mTORC signaling. This phenotype could be rescued by overexpression of AKT but was dependent on kinase activity. Interestingly, expression of the serine/threonine kinase SGK1 was increased following genetic suppression of AKT but only expression of activated SGK1 could rescue the lethal effect of AKT knockdown. SGK1 also increases tumor growth and decreases survival in a BRAFV600E-driven mouse model of melanoma. Despite our results suggesting that key proliferation of melanoma cells is through effects on mTOR, phase II clinical trials of mTOR inhibitors have not shown clinical advantage. This may be due to multiple reasons: firstly, mTOR inhibitors, such as rapamycin, function by destabilization of the mTORC1-Raptor complex while leaving the mTORC2-Rictor complex, intact. Rictor enables mTORC2 to directly phosphorylate Ser473, and facilitates Thr308 phosphorylation by PDK1. As both AKT and SGK are phosphorylated by mTORC2 and PDK1 to facilitate downstream signaling through mTORC1, residual activity of mTOR incompletely suppressed by rapamycin may still be sufficient to drive melanoma progression. Thus, we evaluated second and third generation mTORC inhibitors, including a dual PI3K/mTOR inhibitor, that target both mTORC1 and 2 complexes and lead to sustained suppression of PI3K>AKT signaling. The dual PI3K/mTORC inhibitor, Paxalisib, significantly reduced cell proliferation greater than combination AKT/SGK inhibition and resulted in increased overall survival in a BRAF-driven immunocompetent mouse model of melanoma (p=0.0003 vs vehicle). These results allow insight into compensatory signaling networks upon AKT inhibition and suggest that dual targeting of PI3K and both mTOR complexes may represent an effective and tolerable therapeutic strategy in this disease that could further be combined with standard of care targeted therapy. Citation Format: Gennie L. Parkman, Tursun Turapov, David Kircher, William Burnett, Christopher Stehn, Kayla O'Toole, Katie Culver, Ashley Chadwick, Riley Elmer, Ryan Flaherty, Mona Foth, Karly Stanley, Robert Andtbacka, David Lum, Robert Judson-Torres, Martin McMahon, Sheri Holmen. Newer generation mTOR inhibition represents effective therapeutic strategy for BRAF-mutant melanoma [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 427.
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Narula, Jeremy A. Bravo, and Vito W. Rebecca. "Abstract 419: Elevated Akt/mTOR signaling drives therapy resistance in ALM." Cancer Research 83, no. 7_Supplement (April 4, 2023): 419. http://dx.doi.org/10.1158/1538-7445.am2023-419.
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Abstract Metastatic acral lentiginous melanoma (ALM) is the most lethal subtype of cutaneous melanoma and effective therapies for patients have not been established. Studies revealed a link between the dysregulation of CDK4/6 and ALM mortality, however CDK4/6 inhibitors (CDK4i/6i) have proved ineffective in patients with advanced ALM. The tumor suppressor Rb was recently shown to have a novel suppressive role towards mTORC2. Here, we elucidate the role of a non-canonical tumor suppressor function of Rb in negative regulation of mTOR in CDK4i/6i-resistance. We hypothesize that the loss of Rb induced by CDK4i/6i triggers phosphorylation of Akt and downstream mTORC1 signaling pathways. We characterized baseline activity of the PI3K/AKT/mTOR pathway in a panel of ALM cell lines, finding heterogeneity across signaling. We immunoblotted for key proteins involved in the signal reprogramming hypothesized: pRb, pAkt, pS6 to define activation status and found the loss of Rb phosphorylation preceded the enrichment of pAKT, supporting the non-canonical role of Rb tumor suppression and the Rb-mTORC2 signaling axis as intrinsic CDK4i/6i mechanism. In parallel, we assessed the essential protein-protein interactions required for mechanistic mTORC1 activation—mTOR and Rheb GTPase. The enrichment of these interactions shortly after introducing CDK4i/6i supported our hypothesized mechanism. Translational utility of CDK4i/6i and mTORi dual inhibition was determined via long-term Colony Formation Assays (CFAs) using Palbociclib, rapamycin and sapanisertib (TAK228), a catalytic mTOR inhibitor. We generated Palbociclib (acquired)-resistant ALM cell lines and investigated the pharmacological inhibition of PI3K signaling pathways through immunoblot and colony-formation assays. Concurrent mTORi and CDK4i/6i inhibition showed effective reduction in pRb, pS6, Cyclin D and increases in Cleaved PARP protein, suggesting apoptotic cell death was elevated with combined CDK4i/6i+mTORi treatment. Similarly, CFAs revealed dual inhibition elicited superior antiproliferative effect over the monotherapy treatments. CFAs with acquired-resistance cell lines also showed that combination inhibition decreased colony formation, showing the potential utility of concurrent CDK4i/6i and mTORi as an approach against acquired resistance. Our results show the efficacy of combined inhibition as an anti-tumor strategy. Citation Format: Jeremy A. Bravo Narula, Vito W. Rebecca. Elevated Akt/mTOR signaling drives therapy resistance in ALM [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 419.
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Suryawan, Agus, Asumthia S. Jeyapalan, Renan A. Orellana, Fiona A. Wilson, Hanh V. Nguyen, and Teresa A. Davis. "Leucine stimulates protein synthesis in skeletal muscle of neonatal pigs by enhancing mTORC1 activation." American Journal of Physiology-Endocrinology and Metabolism 295, no. 4 (October 2008): E868—E875. http://dx.doi.org/10.1152/ajpendo.90314.2008.
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Skeletal muscle in the neonate grows at a rapid rate due in part to an enhanced sensitivity to the postprandial rise in amino acids, particularly leucine. To elucidate the molecular mechanism by which leucine stimulates protein synthesis in neonatal muscle, overnight-fasted 7-day-old piglets were treated with rapamycin [an inhibitor of mammalian target of rapamycin (mTOR) complex (mTORC)1] for 1 h and then infused with leucine for 1 h. Fractional rates of protein synthesis and activation of signaling components that lead to mRNA translation were determined in skeletal muscle. Rapamycin completely blocked leucine-induced muscle protein synthesis. Rapamycin markedly reduced raptor-mTOR association, an indicator of mTORC1 activation. Rapamycin blocked the leucine-induced phosphorylation of mTOR, S6 kinase 1 (S6K1), and eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1) and formation of the eIF4E·eIF4G complex and increased eIF4E·4E-BP1 complex abundance. Rapamycin had no effect on the association of mTOR with rictor, a crucial component for mTORC2 activation, or G protein β-subunit-like protein (GβL), a component of mTORC1 and mTORC2. Neither leucine nor rapamycin affected the phosphorylation of AMP-activated protein kinase (AMPK), PKB, or tuberous sclerosis complex (TSC)2, signaling components that reside upstream of mTOR. Eukaryotic elongation factor (eEF)2 phosphorylation was not affected by leucine or rapamycin, although current dogma indicates that eEF2 phosphorylation is mTOR dependent. Together, these in vivo data suggest that leucine stimulates muscle protein synthesis in neonates by enhancing mTORC1 activation and its downstream effectors.
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Damerill, Ian, Kyle K. Biggar, Majida Abu Shehab, Shawn Shun-Cheng Li, Thomas Jansson, and Madhulika B. Gupta. "Hypoxia Increases IGFBP-1 Phosphorylation Mediated by mTOR Inhibition." Molecular Endocrinology 30, no. 2 (February 1, 2016): 201–16. http://dx.doi.org/10.1210/me.2015-1194.
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Abstract In fetal growth restriction (FGR), fetal growth is limited by reduced nutrient and oxygen supply. Insulin-like growth factor I (IGF-I) is a key regulator of fetal growth and IGF binding protein -1(IGFBP-1) is the principal regulator of fetal IGF-I bioavailability. Phosphorylation enhances IGFBP-1's affinity for IGF-I. Hypoxia induces IGFBP-1 hyperphosphorylation, markedly decreasing IGF-I bioavailability. We recently reported that fetal liver IGFBP-1 hyperphosphorylation is associated with inhibition of the mechanistic target of rapamycin (mTOR) in a nonhuman primate model of FGR. Here, we test the hypothesis that IGFBP-1 hyperphosphorylation in response to hypoxia is mediated by mTOR inhibition. We inhibited mTOR either by rapamycin or small interfering RNA (siRNA) targeting raptor (mTOR complex [mTORC]1) and/or rictor (mTORC2) in HepG2 cells cultured under hypoxia (1% O2) or basal (20% O2) conditions. Conversely, we activated mTORC1 or mTORC1+mTORC2 by silencing endogenous mTOR inhibitors (tuberous sclerosis complex 2/DEP-domain-containing and mTOR-interacting protein). Immunoblot analysis demonstrated that both hypoxia and inhibition of mTORC1 and/or mTORC2 induced similar degrees of IGFBP-1 phosphorylation at Ser101/119/169 and reduced IGF-I receptor autophosphorylation. Activation of mTORC1+mTORC2 or mTORC1 alone prevented IGFBP-1 hyperphosphorylation in response to hypoxia. Multiple reaction monitoring-mass spectrometry showed that rapamycin and/or hypoxia increased phosphorylation also at Ser98 and at a novel site Ser174. In silico structural analysis indicated that Ser174 was in close proximity to the IGF-binding site. Together, we demonstrate that signaling through the mTORC1 or mTORC2 pathway is sufficient to induce IGFBP-1 hyperphosphorylation in response to hypoxia. This study provides novel understanding of the cellular mechanism that controls fetal IGFBP-1 phosphorylation in hypoxia, and we propose that mTOR inhibition constitutes a mechanistic link between hypoxia, reduced IGF-I bioavailability and FGR.
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Mparmpakas, Dionisis, Elena Zachariades, Anastasia Goumenou, Yori Gidron, and Emmanouil Karteris. "Placental DEPTOR as a stress sensor during pregnancy." Clinical Science 122, no. 7 (December 7, 2011): 349–59. http://dx.doi.org/10.1042/cs20110378.
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DEPTOR [DEP-domain-containing and mTOR (mammalian target of rapamycin)-interacting protein] is a modulator of mTOR signalling that binds to mTORC (mTOR complex) 1 and mTORC2. However, to date, the precise functions of DEPTOR are not fully elucidated, particularly in reproductive tissues where mTOR acts as a placental nutrient sensor. Pregnancy is associated with major physiological and psychosocial changes and adaptation to these changes is crucial for normal fetal development. In the present study, we tested the hypothesis that maternal stress can affect mTOR signalling at term, and, as a result, influence placental growth. We first investigated the expression of DEPTOR, mTOR, rictor (rapamycin-insensitive companion of mTOR) and raptor (regulatory associated protein of mTOR) from human placentas (n=23) using Q-PCR (quantitative PCR), and correlated these data to days of pregnancy and maternal stress, as well as placental and fetal weight. Maternal and fetal cortisol levels were also measured. JEG-3 and BeWo cells, used as placental in vitro models, were treated with cortisol and DEPTOR expression was assessed using Q-PCR. DEPTOR appears to be the predominant transcript in the human placenta compared with mTOR, rictor and raptor in both term (n=13) and preterm (n=10) placentas as assessed by Q-PCR. There was a significantly lower level only of log-DEPTOR gene expression in the high stress group (−1.34) than in the low stress group (0.07; t20=2.41, P=0.026). Interestingly, mothers with high stress had significantly elevated levels of cortisol (8555 pg/ml) compared with those with low stress (4900 pg/ml). We then tested the hypothesis that cortisol can directly affect DEPTOR expression. When BeWo cells were treated with cortisol 10, 100 and 1000 nM, the expression of DEPTOR was significantly down-regulated by 50, 41 and 39% (all P<0.05) respectively when compared with basal levels. Treatment of JEG-3 cells with cortisol, led to a significant decrease of DEPTOR expression at 100 nM (39%, P<0.05) and at 1000 nM (73%, P<0.01). These novel findings are indicative of a higher order of complexity of DEPTOR signalling in the human placenta that is affected by maternal stress, which could affect pregnancy outcome.
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Laplante, M., and D. M. Sabatini. "mTOR Signaling." Cold Spring Harbor Perspectives in Biology 4, no. 2 (November 30, 2011): a011593. http://dx.doi.org/10.1101/cshperspect.a011593.
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Gohlisch, Christopher. "mTOR-Inhibition." Dialyse aktuell 20, no. 08 (October 10, 2016): 389–92. http://dx.doi.org/10.1055/s-0042-116347.
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Haas, Michael J. "mTOR caveats." Science-Business eXchange 1, no. 6 (March 2008): 132. http://dx.doi.org/10.1038/scibx.2008.132.
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Ernstoff, Marc S. "mTOR Pathway and mTOR Inhibitors in Cancer Therapy." British Journal of Clinical Pharmacology 71, no. 6 (May 12, 2011): 970. http://dx.doi.org/10.1111/j.1365-2125.2011.03919.x.
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Giubellino, Alessio, Petra Bullova, Svenja Nölting, Hana Turkova, James F. Powers, Qingsong Liu, Sylvie Guichard, Arthur S. Tischler, Ashley B. Grossman, and Karel Pacak. "Combined Inhibition of mTORC1 and mTORC2 Signaling Pathways Is a Promising Therapeutic Option in Inhibiting Pheochromocytoma Tumor Growth: In Vitro and In Vivo Studies in Female Athymic Nude Mice." Endocrinology 154, no. 2 (January 10, 2013): 646–55. http://dx.doi.org/10.1210/en.2012-1854.
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Several lines of evidence, including the recent discovery of novel susceptibility genes, point out an important role for the mammalian target of rapamycin (mTOR) signaling pathway in the development of pheochromocytoma. Analyzing a set of pheochromocytomas from patients with different genetic backgrounds, we observed and confirmed a significant overexpression of key mTOR complex (mTORC) signaling mediators. Using selective ATP-competitive inhibitors targeting both mTORC1 and mTORC2, we significantly arrested the in vitro cell proliferation and blocked migration of pheochromocytoma cells as a result of the pharmacological suppression of the Akt/mTOR signaling pathway. Moreover, AZD8055, a selective ATP-competitive dual mTORC1/2 small molecular inhibitor, significantly reduced the tumor burden in a model of metastatic pheochromocytoma using female athymic nude mice. This study suggests that targeting both mTORC1 and mTORC2 is a potentially rewarding strategy and supports the application of selective inhibitors in combinatorial drug regimens for metastatic pheochromocytoma.
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Myint, Khine Nyein, Sean Wallace, Shihe Hou, Maria Zalath, Brian McMorran, Andrew Kwon, and Igor Vivanco. "Abstract 7196: Evaluation of nab-sirolimus in combination with fulvestrant or PI3K pathway inhibitors to overcome resistance in breast cancer cell lines." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7196. http://dx.doi.org/10.1158/1538-7445.am2024-7196.
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Abstract Background: Endocrine therapy (ET) is the standard of care for hormone receptor positive (HR+) breast cancer (BC), but ET resistance develops in most patients (pts). One resistance mechanism involves cross talk between the PI3K-AKT-mTOR and estrogen receptor (ER) signaling pathways, resulting in increased ER signaling and tumor proliferation. This is mitigated by mTOR inhibition as demonstrated by improved outcomes with exemestane plus the mTOR inhibitor (mTORi) everolimus in pts with HR+ advanced BC. While PI3K inhibitors (PI3Ki [e.g. alpelisib]) are efficacious in pts with HR+, PIK3CA-mutated BC, resistance can occur due to acquired genomic alterations in the PI3K-AKT-mTOR pathway. Combination therapy that targets a critical downstream node, mTOR, could delay or overcome acquired resistance due to activation of upstream components of the PI3K-AKT-mTOR pathway. nab-Sirolimus is an intravenously administered, albumin-bound nanoparticle form of the mTORi sirolimus, with significantly greater tumor accumulation, mTOR target suppression, and improved antitumor effects than oral mTORis in nonclinical tumor models. We evaluated the antiproliferative and cytotoxic effects of nab-sirolimus in combination with ET or PI3Kis in BC cell lines. Methods: HR+, PI3K-mutated BC cell lines (MCF7 or MDA-MB-361) were incubated for 5 days with increasing concentrations of nab-sirolimus and the selective ER degrader fulvestrant. MDA-MB-361 cells or HR-negative (HR−), PI3K-mutated BC cells, MDA-MD-453, were incubated for 5 days with increasing concentrations of nab-sirolimus and PI3K-AKT-mTOR pathway inhibitors gedatolisib or alpelisib. Antiproliferative/cytotoxic effects of single-agent and combination treatment were assessed via an automated trypan blue exclusion assay. Results: Addition of 20 or 80 nM nab-sirolimus to fulvestrant (12.5-500 nM) markedly decreased cell viability and nearly doubled cell death in MCF7 and MDA-MB-361 cells. Antiproliferative effects of low-dose gedatolisib (2.5-10 nM) were enhanced by 61-71% when nab-sirolimus (20 or 80 nM) was added to MDA-MB-453 cells. While low doses (2.5, 5, and 10 nM) of gedatolisib alone led to limited cytotoxicity (4.2-9.6%), up to 48.9% of cell death occurred when 20 or 80 nM nab-sirolimus was added. Results were similar with alpelisib (1 uM) plus nab-sirolimus (20 or 80 nM). Western blot showed increased p4EBP1 in response to fulvestrant or PI3Ki treatment, which was reversed with the addition of nab-sirolimus. Conclusions: nab-Sirolimus enhanced the cytotoxic effects of fulvestrant in HR+ BC cells and of PI3Kis in HR+ and HR− BC cells. Addition of nab-sirolimus to ET or other PI3K-AKT-mTOR pathway inhibitors may overcome mechanisms of resistance; further exploration is warranted to elucidate clinical relevance. Citation Format: Khine Nyein Myint, Sean Wallace, Shihe Hou, Maria Zalath, Brian McMorran, Andrew Kwon, Igor Vivanco. Evaluation of nab-sirolimus in combination with fulvestrant or PI3K pathway inhibitors to overcome resistance in breast cancer cell lines [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 7196.
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Acklin, Joshua, Mitra Azadniv, Scott Portwood, Kimberly Lacagnina, Charlotte Beers, Eunice S. Wang, and Jane L. Liesveld. "Optimizing Effects of mTOR Inhibition in Acute Myelogenous Leukemia." Blood 126, no. 23 (December 3, 2015): 4930. http://dx.doi.org/10.1182/blood.v126.23.4930.4930.
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Abstract Introduction : Mammalian target of rapamycin (mTOR) signaling has previously been identified as a possible therapeutic target in acute myelogenous leukemia (AML), as the PI3K/AKT/mTOR pathway has been shown to be upregulated in blasts of up to 90% of AML cases through the constitutive loss of the tumor suppressor PTEN. The activation of this pathway is implicated in synthesis of prosurvival transcription and translational factors responsible for cellular resistance to apoptosis, resistance to chemotherapy, and enhanced survival in the marrow microenvironment. Unfortunately, exploitation of this pathway has been largely ineffective in clinical studies. A second mTOR complex (mTORC2) will reestablish the activation of the first when the first mTOR complex (mTORC1) is shut down under treatment with traditional rapalogs, such as rapamycin and everolimus. Additionally, the cellular process of autophagy has been postulated to be a protective mechanism for leukemic blasts during treatment with mTOR inhibitors, therefore decreasing their efficacy. For these reasons, this work explores means to optimize mTOR pathway inhibition by examining effects of dual mTORC inhibition (OSI027), dual PI3K/mTOR inhibition (BEZ235/Dactilosib), combination of mTOR inhibitors with a histone deacetylase inhibitor with ability to inhibit AKT (LBH589/Panobinostat), and the combination of mTOR inhibitors with hypomethylating agents able to overcome the hypermethylation of mTOR pathway components such as TSC1, TSC2 and PTEN (decitabine/5-azacytidine). Materials and Methods : Primary AML leukapheresis samples obtained with informed consent were cultured for 48 hours in the presence of OSI027, LBH589 (Novartis), BEZ235 (Novartis), decitabine, or OSI027 in combination with each of these individual inhibitors and compared with control culture conditions. Cells were stained with annexinV and DAPI as previously described, and the percent of living, pre-apoptotic, necrotic and dead cells were determined via flow cytometry. Synergy calculations were completed using Calcusyn™ software as described by Chao and Talalay (1977). Autophagic flux was determined in the OSI027 and LBH589 combination exposure via flow cytometry using anti-LC3. Lastly, protein expression under treatment with various combinations was determined via standard western blotting techniques. Results: The MV411 AML cell line was utilized to establish efficacy of combination exposures. These cells expressed phosphorylated (p)Akt (ser 473), p4EBP1, and pmTOR. OSI027 10µM, LBH589 1µM, and BEZ235 10nM were able to inhibit pmTOR, pAKT, and p4EBP1 expression as determined by western blotting. In the MV411 cell line, IC50s were determined, and combination indices were determined for OSI027+BEZ235, panobinostat+BEZ235, and panobinostat+OSI027; all of which demonstrated synergy. In primary AML samples, the combination of OSI027 10uM and LBH589 10nM significantly increased the percentage of dead cells in comparison to OSI027 treatment alone. Additionally in primary AML blasts, pmTOR and pAKT expression were decreased in the combination of OSI027 and LBH589 when compared to single agent treatment via western blot. The combination of OSI027 and LBH589 demonstrated a significant reduction in the autophagic flux in comparison to OSI027 treatment alone, suggesting an anti-autophagic effect, which correlates with the increased rates of cellular death in the combination. It was also found in AML cell lines that the combination of 10 µM azacytidine and 100 nM rapamycin resulted in synergistic suppression of U937, MV411, and KG1a survival as measured by MTT. No synergy was noted in the HL60 cell line. This combination effectively suppressed CFU-L in primary AML cases and suppressed p70S6K and p4EBP1 expression more than either agent alone by western blotting. The combination of decitabine 500nM with OSI027 10uM did not demonstrate an increase in apoptotic cells in primary blasts compared to OSI027 alone. Conclusions : Based on these findings, we conclude that mTOR inhibition in AML cell lines and primary samples can be enhanced through dual mTORC inhibition, PI3K modulation, and histone deacetylase inhibition. This may occur through suppression of activated pathway mediators or through suppression of autophagic flux. These results suggest that there is merit in exploring these combinations for therapeutic potential in AML. Disclosures Portwood: ImmunoGen: Research Funding. Wang:ImmunoGen: Research Funding.
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Wang, Tianyi, Kaiqi Long, Yang Zhou, Xiaoding Jiang, Jinzhao Liu, John H. C. Fong, Alan S. L. Wong, Wai-Lung Ng, and Weiping Wang. "Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy." ACS Pharmacology & Translational Science 5, no. 3 (February 8, 2022): 149–55. http://dx.doi.org/10.1021/acsptsci.1c00230.
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Dowling, Ryan J. O., Ivan Topisirovic, Bruno D. Fonseca, and Nahum Sonenberg. "Dissecting the role of mTOR: Lessons from mTOR inhibitors." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1804, no. 3 (March 2010): 433–39. http://dx.doi.org/10.1016/j.bbapap.2009.12.001.
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Gomez-Pinillos, Alejandro, and Anna C. Ferrari. "mTOR Signaling Pathway and mTOR Inhibitors in Cancer Therapy." Hematology/Oncology Clinics of North America 26, no. 3 (June 2012): 483–505. http://dx.doi.org/10.1016/j.hoc.2012.02.014.
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Li, Na, Jie Chen, Qiang Liu, Hongyi Qu, Xiaoqing Yang, Peng Gao, Yao Wang, Huayu Gao, Hong Wang, and Zuohui Zhao. "Prognostic significance and tumor-immune infiltration of mTOR in clear cell renal cell carcinoma." PeerJ 9 (August 17, 2021): e11901. http://dx.doi.org/10.7717/peerj.11901.
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Mammalian target of rapamycin (mTOR), a serine/threonine kinase involved in cell proliferation, survival, metabolism and immunity, was reportedly activated in various cancers. However, the clinical role of mTOR in renal cell carcinoma (RCC) is controversial. Here we detected the expression and prognosis of total mTOR and phosphorylated mTOR (p-mTOR) in clear cell RCC (ccRCC) patients, and explored the interactions between mTOR and immune infiltrates in ccRCC. The protein level of mTOR and p-mTOR was determined by western blotting (WB), and their expression was evaluated in 145 ccRCC and 13 non-tumor specimens by immunohistochemistry (IHC). The relationship to immune infiltration of mTOR was further investigated using TIMER and TISIDB databases, respectively. WB demonstrated the ratio of p-mTOR to mTOR was higher in ccRCC than adjacent specimens (n = 3), and IHC analysis elucidated that p-mTOR expression was positively correlated with tumor size, stage and metastasis status, and negatively correlated with cancer-specific survival (CSS). In univariate analysis, high grade, large tumor, advanced stage, metastasis, and high p-mTOR expression were recognized as prognostic factors of poorer CSS, and multivariate survival analysis elucidated that tumor stage, p-mTOR and metastasis were of prognostic value for CSS in ccRCC patients. Further TIMER and TISIDB analyses uncovered that mTOR gene expression was significantly associated with numerous immune cells and immunoinhibitors in patients with ccRCC. Collectively, these findings revealed p-mTOR was identified as an independent predictor of poor survival, and mTOR was associated with tumor immune infiltrates in ccRCC patients, which validated mTOR could be implicated in the initiation and progression of ccRCC.
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Qian, Jiayi, Siyuan Su, and Pengda Liu. "Experimental Approaches in Delineating mTOR Signaling." Genes 11, no. 7 (July 2, 2020): 738. http://dx.doi.org/10.3390/genes11070738.
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The mTOR signaling controls essential biological functions including proliferation, growth, metabolism, autophagy, ageing, and others. Hyperactivation of mTOR signaling leads to a plethora of human disorders; thus, mTOR is an attractive drug target. The discovery of mTOR signaling started from isolation of rapamycin in 1975 and cloning of TOR genes in 1993. In the past 27 years, numerous research groups have contributed significantly to advancing our understanding of mTOR signaling and mTOR biology. Notably, a variety of experimental approaches have been employed in these studies to identify key mTOR pathway members that shape up the mTOR signaling we know today. Technique development drives mTOR research, while canonical biochemical and yeast genetics lay the foundation for mTOR studies. Here in this review, we summarize major experimental approaches used in the past in delineating mTOR signaling, including biochemical immunoprecipitation approaches, genetic approaches, immunofluorescence microscopic approaches, hypothesis-driven studies, protein sequence or motif search driven approaches, and bioinformatic approaches. We hope that revisiting these distinct types of experimental approaches will provide a blueprint for major techniques driving mTOR research. More importantly, we hope that thinking and reasonings behind these experimental designs will inspire future mTOR research as well as studies of other protein kinases beyond mTOR.
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Saddadi, Fereshteh, and Mohammad Hassan Fallahkohan. "Everolimus induced pulmonary thromboembolism after kidney transplantation; a case report." Journal of Nephropathology 11, no. 1 (June 5, 2021): e11-e11. http://dx.doi.org/10.34172/jnp.2022.11.
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Choice of maintenance immunosuppressive therapy after renal transplantation is important for graft survival. However, complication may also occur. Venous thromboembolic event with the mTOR inhibitor (mTORi) everolimus is a rare but life-threatening complication. Here we describe a renal transplant recipient who developed pulmonary thromboembolism.
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Song, Xiaoxiao, Yoichiro Kusakari, Chun-Yang Xiao, Stuart D. Kinsella, Michael A. Rosenberg, Marielle Scherrer-Crosbie, Kenta Hara, Anthony Rosenzweig, and Takashi Matsui. "mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy." American Journal of Physiology-Cell Physiology 299, no. 6 (December 2010): C1256—C1266. http://dx.doi.org/10.1152/ajpcell.00338.2010.
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Previous studies have suggested that inhibition of the mammalian target of rapamycin (mTOR) by rapamycin suppresses myocardial hypertrophy. However, the role of mTOR in the progression of cardiac dysfunction in pathological hypertrophy has not been fully defined. Interestingly, recent reports indicate that the inflammatory response, which plays an important role in the development of heart failure, is enhanced by rapamycin under certain conditions. Our aim in this study was to determine the influence of mTOR on pathological hypertrophy and to assess whether cardiac mTOR regulates the inflammatory response. We generated transgenic mice with cardiac-specific overexpression of wild-type mTOR (mTOR-Tg). mTOR-Tg mice were protected against cardiac dysfunction following left ventricular pressure overload induced by transverse aortic constriction (TAC) ( P < 0.01) and had significantly less interstitial fibrosis compared with littermate controls (WT) at 4 wk post-TAC ( P < 0.01). In contrast, TAC caused cardiac dysfunction in WT. At 1 wk post-TAC, the proinflammatory cytokines interleukin (IL)-1β and IL-6 were significantly increased in WT mice but not in mTOR-Tg mice. To further characterize the effects of mTOR activation, we exposed HL-1 cardiomyocytes transfected with mTOR to lipopolysaccharide (LPS). mTOR overexpression suppressed LPS-induced secretion of IL-6 ( P < 0.001), and the mTOR inhibitors rapamycin and PP242 abolished this inhibitory effect of mTOR. In addition, mTOR overexpression reduced NF-κB-regulated transcription in HL-1 cells. These data suggest that mTOR mitigates adverse outcomes of pressure overload and that this cardioprotective effect of mTOR is mediated by regulation of the inflammatory reaction.
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Avruch, Joseph, Xiaomeng Long, Yenshou Lin, Sara Ortiz-Vega, Joseph Rapley, Angela Papageorgiou, Noriko Oshiro, and Ushio Kikkawa. "Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor1." Biochemical Society Transactions 37, no. 1 (January 20, 2009): 223–26. http://dx.doi.org/10.1042/bst0370223.
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The signalling function of mTOR complex 1 is activated by Rheb-GTP, which controls the catalytic competence of the mTOR (mammalian target of rapamycin) kinase domain by an incompletely understood mechanism. Rheb can bind directly to the mTOR kinase domain, and association with inactive nucleotide-deficient Rheb mutants traps mTOR in a catalytically inactive state. Nevertheless, Rheb-GTP targets other than mTOR, such as FKBP38 (FK506-binding protein 38) and/or PLD1 (phospholipase D1), may also contribute to mTOR activation. Once activated, the mTOR catalytic domain phosphorylates substrates only when they are bound to raptor (regulatory associated protein of mTOR), a separate polypeptide within the complex. The mechanism of insulin/nutrient stimulation of mTOR complex 1 signalling, in addition to Rheb-GTP activation of the mTOR catalytic function, also involves a stable modification of the configuration of mTORC1 (mTOR complex 1) that increases access of substrates to their binding site on the raptor polypeptide. The mechanism underlying this second step in the activation of mTORC1 is unknown.
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Sonis, Stephen T., and Alessandro Villa. "A New Hypothesis Describing the Pathogenesis of Oral Mucosal Injury Associated with the Mammalian Target of Rapamycin (mTOR) Inhibitors." Cancers 16, no. 1 (December 22, 2023): 68. http://dx.doi.org/10.3390/cancers16010068.
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It has been 24 years since rapamycin (sirolimus) was approved to mitigate solid organ transplant rejection and 16 years since mTOR (mammalian/mechanistic target of rapamycin) inhibitors reached patients as a cancer therapy. While the clinical benefits of mTOR inhibitors (mTORi) are robust, so too are their toxicities. Among the most common issues is the development of ulcers of the oral mucosa (mTOR-inhibitor associated stomatitis; mIAS). These lesions are distinct from those of other anti-cancer agents, occur with regularity, and impact patient outcomes. mIAS’ pathogenesis has been the subject of speculation, and its similar presentation to recurrent aphthous stomatitis (RAS) has led to the hypothesis that it might serve as a surrogate to better understand RAS. Based on a review of the literature, the current manuscript provides a hypothesis regarding the mechanisms by which mTORis uniquely initiate mucosal injury and an explanation for the observation that steroids (also an immunosuppressive) are effective in its treatment through a non-immunologic mechanism. Unexplained unique features of mIAS are discussed in this review in the context of future investigation.
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Xu, Song, Li Li, Min Li, Mengli Zhang, Mei Ju, Xu Chen, and Heng Gu. "Impact on Autophagy and Ultraviolet B Induced Responses of Treatment with the MTOR Inhibitors Rapamycin, Everolimus, Torin 1, and pp242 in Human Keratinocytes." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–21. http://dx.doi.org/10.1155/2017/5930639.
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The mechanistic target of Rapamycin (MTOR) protein is a crucial signaling regulator in mammalian cells that is extensively involved in cellular biology. The function of MTOR signaling in keratinocytes remains unclear. In this study, we detected the MTOR signaling and autophagy response in the human keratinocyte cell line HaCaT and human epidermal keratinocytes treated with MTOR inhibitors. Moreover, we detected the impact of MTOR inhibitors on keratinocytes exposed to the common carcinogenic stressors ultraviolet B (UVB) and UVA radiation. As a result, keratinocytes were sensitive to the MTOR inhibitors Rapamycin, everolimus, Torin 1, and pp242, but the regulation of MTOR downstream signaling was distinct. Next, autophagy induction only was observed in HaCaT cells treated with Rapamycin. Furthermore, we found that MTOR signaling was insensitive to UVB but sensitive to UVA radiation. UVB treatment also had no impact on the inhibition of MTOR signaling by MTOR inhibitors. Finally, MTOR inhibition by Rapamycin, everolimus, or pp242 did not affect the series of biological events in keratinocytes exposed to UVB, including the downregulation of BiP and PERK, activation of Histone H2A and JNK, and cleavage of caspase-3 and PARP. Our study demonstrated that MTOR inhibition in keratinocytes cannot always induce autophagy, and the MTOR pathway does not play a central role in the UVB triggered cellular response.
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Patel, Raina A., Imran Ahmad, Christine E. Sheehan, Jeffrey S. Ross, George D. Wilner, Alida Hayner-Buchan, and Tipu Nazeer. "Expression of Phosphorylated mTOR (p-mTOR) Correlates with Advanced Stage in Diffuse Large B-Cell Lymphomas." Blood 110, no. 11 (November 16, 2007): 1573. http://dx.doi.org/10.1182/blood.v110.11.1573.1573.
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Abstract Background: The mammalian target of rapamycin (mTOR), plays a major role in regulating cell growth. The activated form of mTOR (phosphorylated mTOR) mediates its effects through mitogen and nutrient dependant signal transduction that regulates mRNA translation. Levels of phosphorylated mTOR (p-mTOR) have been shown to correlate with cell proliferation and inhibition of the mTOR pathway has shown therapeutic promise in some tumors. Information on the role of p-mTOR in hematopoietic malignancies is limited. The aim of the current study is to evaluate the expression of p-mTOR in diffuse large B-cell lymphomas. Design: Formalin-fixed paraffin-embedded tissue sections from 45 DLBCLs were immunostained by an automated method (Ventana Medical Systems, Inc., Tucson, AZ) using p-mTOR rabbit monoclonal antibody (IHC specific Ser2448/49F9; Cell Signaling Technology, Inc., Danvers, MA). Immunoreactivity (cytoplasmic with membranous accentuation) was semiquantitatively assessed based on p-mTOR stain intensity (none, weak, moderate, intense) and distribution (none, focal<10%, regional 11–50%, diffuse>50%). Staining was correlated with histologic and prognostic factors. Results: Membranous/cytoplasmic p-mTOR immunoreactivity was present in 88% of DLBCLs and correlated with advanced tumor stage, with 100% advanced stage versus 73% low stage tumors expressing membranous/cytoplasmic p-mTOR protein (p=0.002). One hundred percent of cases with complete absence of p-mTOR immunoreactivity were low stage DLBCLs. Conclusion: Membranous/cytoplasmic protein expression of p-mTOR correlates with advanced stage in DLBCL. Activated mTOR may play an important role in disease progression and provide a target for therapy in DLBCL. Further studies of the m-TOR pathway in hematopoietic malignancies appear warranted.
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Goodman, Craig A., Man Hing Miu, John W. Frey, Danielle M. Mabrey, Hannah C. Lincoln, Yejing Ge, Jie Chen, and Troy A. Hornberger. "A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy." Molecular Biology of the Cell 21, no. 18 (September 15, 2010): 3258–68. http://dx.doi.org/10.1091/mbc.e10-05-0454.
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It has been widely proposed that signaling by mammalian target of rapamycin (mTOR) is both necessary and sufficient for the induction of skeletal muscle hypertrophy. Evidence for this hypothesis is largely based on studies that used stimuli that activate mTOR via a phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)-dependent mechanism. However, the stimulation of signaling by PI3K/PKB also can activate several mTOR-independent growth-promoting events; thus, it is not clear whether signaling by mTOR is permissive, or sufficient, for the induction of hypertrophy. Furthermore, the presumed role of mTOR in hypertrophy is derived from studies that used rapamycin to inhibit mTOR; yet, there is very little direct evidence that mTOR is the rapamycin-sensitive element that confers the hypertrophic response. In this study, we determined that, in skeletal muscle, overexpression of Rheb stimulates a PI3K/PKB-independent activation of mTOR signaling, and this is sufficient for the induction of a rapamycin-sensitive hypertrophic response. Transgenic mice with muscle specific expression of various mTOR mutants also were used to demonstrate that mTOR is the rapamycin-sensitive element that conferred the hypertrophic response and that the kinase activity of mTOR is necessary for this event. Combined, these results provide direct genetic evidence that a PI3K/PKB-independent activation of mTOR signaling is sufficient to induce hypertrophy. In summary, overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hypertrophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confers the hypertrophy, and the kinase activity of mTOR is necessary for this event.
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Hall, Michael N. "On mTOR nomenclature." Biochemical Society Transactions 41, no. 4 (July 18, 2013): 887–88. http://dx.doi.org/10.1042/bst20130092.
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In the present article, I discuss recent developments in the naming of the TOR (target of rapamycin) protein. In particular, I address the issue of mammalian target of rapamycin (mTOR) versus the newer mechanistic target of rapamycin (MTOR). mTOR is the name given by the TOR community almost two decades ago and widely used ever since. MTOR is a name recently imposed on the TOR community by database curators and used mainly by newcomers. I argue that MTOR is causing needless confusion in the field, and conclude that one should use the name mTOR.
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Ho, Dong-Ru, Shih-Horng Su, Pey-Jium Chang, Wei-Yu Lin, Yun-Ching Huang, Jian-Hui Lin, Kuo-Tsai Huang, Wai-Nga Chan, and Chih-Shou Chen. "Biodegradable Stent with mTOR Inhibitor-Eluting Reduces Progression of Ureteral Stricture." International Journal of Molecular Sciences 22, no. 11 (May 26, 2021): 5664. http://dx.doi.org/10.3390/ijms22115664.
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In this study, we investigated the effect of mTOR inhibitor (mTORi) drug-eluting biodegradable stent (DE stent), a putative restenosis-inhibiting device for coronary artery, on thermal-injury-related ureteral stricture in rabbits. In vitro evaluation confirmed the dose-dependent effect of mTORi, i.e., rapamycin, on fibrotic markers in ureteral component cell lines. Upper ureteral fibrosis was induced by ureteral thermal injury in open surgery, which was followed by insertion of biodegradable stents, with or without rapamycin drug-eluting. Immunohistochemistry and Western blotting were performed 4 weeks after the operation to determine gross anatomy changes, collagen deposition, expression of epithelial–mesenchymal transition markers, including Smad, α-SMA, and SNAI 1. Ureteral thermal injury resulted in severe ipsilateral hydronephrosis. The levels of type III collagen, Smad, α-SMA, and SNAI 1 were increased 28 days after ureteral thermal injury. Treatment with mTORi-eluting biodegradable stents significantly attenuated thermal injury-induced urinary tract obstruction and reduced the level of fibrosis proteins, i.e., type III collagen. TGF-β and EMT signaling pathway markers, Smad and SNAI 1, were significantly modified in DE stent-treated thermal-injury-related ureteral stricture rabbits. These results suggested that intra-ureteral administration of rapamycin by DE stent provides modification of fibrosis signaling pathway, and inhibiting mTOR may result in fibrotic process change.
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Wang, Xuerong, Ping Yue, Chi-Bun Chan, Keqiang Ye, Takeshi Ueda, Rie Watanabe-Fukunaga, Rikiro Fukunaga, Haian Fu, Fadlo R. Khuri, and Shi-Yong Sun. "Inhibition of Mammalian Target of Rapamycin Induces Phosphatidylinositol 3-Kinase-Dependent and Mnk-Mediated Eukaryotic Translation Initiation Factor 4E Phosphorylation." Molecular and Cellular Biology 27, no. 21 (August 27, 2007): 7405–13. http://dx.doi.org/10.1128/mcb.00760-07.
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ABSTRACT The initiation factor eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in initiating translation of mRNAs, including those encoding oncogenic proteins. Therefore, eIF4E is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eIF4E (usually at Ser209) increases its binding affinity for the cap of mRNA and may also favor its entry into initiation complexes. Mammalian target of rapamycin (mTOR) inhibitors suppress cap-dependent translation through inhibition of the phosphorylation of eIF4E-binding protein 1. Paradoxically, we have shown that inhibition of mTOR signaling increases eIF4E phosphorylation in human cancer cells. In this study, we focused on revealing the mechanism by which mTOR inhibition increases eIF4E phosphorylation. Silencing of either mTOR or raptor could mimic mTOR inhibitors’ effects to increase eIF4E phosphorylation. Moreover, knockdown of mTOR, but not rictor or p70S6K, abrogated rapamycin's ability to increase eIF4E phosphorylation. These results indicate that mTOR inhibitor-induced eIF4E phosphorylation is secondary to mTOR/raptor inhibition and independent of p70S6K. Importantly, mTOR inhibitors lost their ability to increase eIF4E phosphorylation only in cells where both Mnk1 and Mnk2 were knocked out, indicating that mTOR inhibitors increase eIF4E phosphorylation through a Mnk-dependent mechanism. Given that mTOR inhibitors failed to increase Mnk and eIF4E phosphorylation in phosphatidylinositol 3-kinase (PI3K)-deficient cells, we conclude that mTOR inhibition increases eIF4E phosphorylation through a PI3K-dependent and Mnk-mediated mechanism. In addition, we also suggest an effective therapeutic strategy for enhancing mTOR-targeted cancer therapy by cotargeting mTOR signaling and Mnk/eIF4E phosphorylation.
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Klümpen, Heinz‐Josef, Jos H. Beijnen, Howard Gurney, and Jan H. M. Schellens. "Inhibitors of mTOR." Oncologist 15, no. 12 (December 2010): 1262–69. http://dx.doi.org/10.1634/theoncologist.2010-0196.
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Larochelle, Stéphane. "mTOR: restricted access." Nature Structural & Molecular Biology 20, no. 6 (June 2013): 656. http://dx.doi.org/10.1038/nsmb.2610.
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Allison, Susan J. "mTOR in FSGS." Nature Reviews Nephrology 13, no. 5 (March 27, 2017): 260. http://dx.doi.org/10.1038/nrneph.2017.42.
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Harrison, Charlotte. "Actively targeting mTOR." Nature Reviews Drug Discovery 9, no. 3 (March 2010): 193. http://dx.doi.org/10.1038/nrd3118.
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Fulmer, Tim. "Ketamine meets mTOR." Science-Business eXchange 3, no. 34 (September 2010): 1032. http://dx.doi.org/10.1038/scibx.2010.1032.
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