Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1
Isaam Ben Sahra,Claire Regazzetti,Guillaume Robert,Kathiane Laurent,Yannick Le Marchand-Brustel,Patrick Auberger,Jean-François Tanti,Sophie Giorgetti-Peraldi,Frédéric Bost +8 more
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TLDR
RedD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, is identified as a new molecular target of metformin and inhibition of REDD1 reverses meetformin-induced cell-cycle arrest and significantly protects from the deleterious effects of met formin on cell transformation.Abstract:
Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by AMP-activated protein kinase (AMPK). We identified REDD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, as a new molecular target of metformin. We show that metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1(-/-) cells, abrogates metformin inhibition of mTOR. Importantly, inhibition of REDD1 reverses metformin-induced cell-cycle arrest and significantly protects from the deleterious effects of metformin on cell transformation. Finally, we show the contribution of p53 in mediating metformin action in prostate cancer cells. These results highlight the p53/REDD1 axis as a new molecular target in anticancer therapy in response to metformin treatment.read more
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Cellular and molecular mechanisms of metformin: an overview
Benoit Viollet,Benoit Viollet,Benoit Viollet,Bruno Guigas,Nieves Sanz Garcia,Nieves Sanz Garcia,Nieves Sanz Garcia,Jocelyne Leclerc,Jocelyne Leclerc,Jocelyne Leclerc,Marc Foretz,Marc Foretz,Marc Foretz,Fabrizio Andreelli +13 more
TL;DR: Emerging new therapeutic areas for metformin will be reviewed together with recent findings from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D.
Journal ArticleDOI
mTOR: a pharmacologic target for autophagy regulation
Young Chul Kim,Kun-Liang Guan +1 more
TL;DR: An overview of the mTOR signaling pathway, the mechanisms of m TOR in autophagy regulation, and the clinical implications of mTOR inhibitors in disease treatment are provided.
Journal ArticleDOI
Metformin improves healthspan and lifespan in mice
Alejandro Martin-Montalvo,Evi M. Mercken,Sarah J. Mitchell,Sarah J. Mitchell,Sarah J. Mitchell,Hector H. Palacios,Patricia L. Mote,Morten Scheibye-Knudsen,Ana P. Gomes,Theresa M. Ward,Robin K. Minor,Marie-José Blouin,Matthias Schwab,Michael Pollak,Yongqing Zhang,Yinbing Yu,Kevin G. Becker,Vilhelm A. Bohr,Donald K. Ingram,David A. Sinclair,Norman S. Wolf,Stephen R. Spindler,Michel Bernier,Rafael de Cabo +23 more
TL;DR: It is shown that long-term treatment with metformin starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic.
Journal ArticleDOI
Signal integration by mTORC1 coordinates nutrient input with biosynthetic output
TL;DR: The role of mTORC1 is discussed, as a conduit between cellular growth conditions and the anabolic processes that promote cell growth, which provides molecular insights into the integrated sensing mechanisms by which diverse cellular signals converge to control cell physiology.
Journal ArticleDOI
Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality.
Emily J. Gallagher,Derek LeRoith +1 more
TL;DR: The current epidemiology, basic science, and clinical data that link obesity, diabetes, and cancer are discussed and how treating obesity and type 2 diabetes could also reduce cancer risk and improve outcomes are discussed.
References
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Journal ArticleDOI
Role of AMP-activated protein kinase in mechanism of metformin action
Gaochao Zhou,Robert W. Myers,Ying Li,Yuli Chen,Xiaolan Shen,Judy Fenyk-Melody,Margaret Wu,John Ventre,Thomas W. Doebber,Nobuharu Fujii,Nicolas Musi,Michael F. Hirshman,Laurie J. Goodyear,David E. Moller +13 more
TL;DR: It is reported that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed.
Journal ArticleDOI
Metformin and reduced risk of cancer in diabetic patients
TL;DR: It is hypothesised that metformin use in patients with type 2 diabetes may reduce their risk of cancer and tested this hypothesis using record linkage databases developed in Tayside, Scotland: a diabetes clinical information system (DARTS) and a database of dispensed prescriptions (MEMO).
Journal ArticleDOI
Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
James Brugarolas,Kui Lei,Rebecca L. Hurley,Brendan D. Manning,Jan H. Reiling,Ernst Hafen,Lee A. Witters,Leif W. Ellisen,William G. Kaelin,William G. Kaelin +9 more
TL;DR: It is shown that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the Hypoxia-inducible gene REDD1/RTP801 to be inhibited, and that down-regulation of mTOR activity by hyp oxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxIA-Inducible REDD 1 gene.
Journal ArticleDOI
The TSC1-TSC2 complex: a molecular switchboard controlling cell growth.
TL;DR: The present review focuses on the molecular details of TSC1-TSC2 complex regulation and function as it relates to the control of Rheb and mTORC1.
Journal ArticleDOI
Metformin Is an AMP Kinase–Dependent Growth Inhibitor for Breast Cancer Cells
TL;DR: It is shown here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells, which provides evidence for a mechanism that may contribute to the antineoplastic effects of met formin suggested by recent population studies and justifies further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment.