Metformin, Independent of AMPK, Inhibits mTORC1 in a Rag GTPase-Dependent Manner

Kalender, Adem; Selvaraj, Anand; Kim, So Young; Gulati, Pawan; Brûlé, Sophie; Viollet, Benoı̂t; Kemp, Bruce E.; Bardeesy, Nabeel; Dennis, Patrick B.; Schlager, John J.; Marette, André; Kozma, Sara C.; Thomas, George

doi:10.1016/j.cmet.2010.03.014

Cited by 747 publications

(599 citation statements)

References 60 publications

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“…Additionally, it might also inhibit tumor progression by AMPK-mediated inhibition of mTORC1, and possibly also by a Rac GTPase-dependent and AMPK-independent mechanism (Ref. 155). Combined cancer therapy with metformin and drugs targeting the PI3K/AKT pathway might result in the synergistic inhibition of mTORC1.…”

Section: Metformin and Ampk In Clinical Usementioning

confidence: 99%

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

Schultze

Hemmings

Nießen

et al. 2012

Expert Rev. Mol. Med.

371

279

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New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications.

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Section: Metformin and Ampk In Clinical Usementioning

confidence: 99%

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

Schultze

Hemmings

Nießen

et al. 2012

Expert Rev. Mol. Med.

371

279

View full text Add to dashboard Cite

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“…The mechanism that leads to mTOR inactivation on glucose withdrawal is still incompletely characterized. It was first demonstrated to be AMPK dependent, but recently it has been reported that agents that reduce ATP levels can inactivate mTOR in the absence of AMPK (Gwinn et al, 2008;Kalender et al, 2010). Besides ATP levels, other good indicators of low glucose availability and energy stress are a decrease in the NADH/NAD þ ratio and a general decrease in protein acetylation.…”

Section: Sensing Glucose Deprivationmentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio-and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

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“…The difference relates to the direct inhibition of mTOR (without concomitant energy stress) by currently used mTOR inhibitors, as compared with mTOR inhibition in the setting of biguanide-induced energetic stress ( 56 ) or biguanide effects involving a Rag GTPase-dependent mechanism ( 103 ). It is important to emphasize, however, that pharmacokinetic factors and integrity of AMPK signaling will infl uence the extent of biguanide-induced mTOR inhibition in a tissue-specifi c manner.…”

Section: Effects At the Whole-organism Levelmentioning

confidence: 99%

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

2012

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Laboratory research and pharmacoepidemiology are providing converging evidence that the widely used antidiabetic drug metformin has antineoplastic activity, but there are caveats. Although population studies suggest that metformin exposure is associated with reduced cancer risk and/or improved prognosis, these data are mostly retrospective and nonrandomized. Laboratory models show antineoplastic activity, but metformin concentrations used in many experiments exceed those achieved with conventional doses used for diabetes treatment. Ongoing translational research should be useful in guiding design of clinical trials, not only to evaluate metformin at conventional antidiabetic doses, where reduction of elevated insulin levels may contribute to antineoplastic activity for certain subsets of patients, but also to explore more aggressive dosing of biguanides, which may lead to reprogramming of energy metabolism in a manner that could provide important opportunities for synthetic lethality through rational drug combinations or in the context of genetic lesions associated with hypersensitivity to energetic stress. Significance: There are tantalizing clues that justify the investigation of antineoplastic activities of biguanides. The complexity of their biologic effects requires further translational research to guide clinical trial design. Cancer Discov; 2(9); 778–90. ©2012 AACR.

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Metformin, Independent of AMPK, Inhibits mTORC1 in a Rag GTPase-Dependent Manner

Cited by 747 publications

References 60 publications

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

Sugar-free approaches to cancer cell killing

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

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