Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1

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 À/À 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. Cancer Res; 71(13); 4366-72. '2011 AACR.

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

“…2A and Supplementary Figure S2). Although biguanide, the most widely used antidiabetic drug, is known to exert its anticancer effects through activation of AMPK and consequent inhibition of the mTOR pathway, 32,33 this AMPK-dependent mTOR inhibition was not observed in our experiment.…”

Mechanism of Metformin-dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer

“…The antineoplastic activities of metformin in cancer cell lines includes the inhibition of several pathways and genes that are important for cancer cell proliferation, survival, migration, and invasion (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Metformin down-regulates expression of Sp1, Sp3, and Sp4 and several pro-oncogenic Sp-regulated genes, and this study shows that inhibition of mTOR signaling and RAS activation by metformin in pancreatic cancer cells is also due to decreased expression of the Sp-regulated upstream receptor tyrosine kinases (RTKs) IGF-1R and EGFR, respectively.…”

“…The potential clinical applications for metformin in cancer chemotherapy also stems from studies on the anticancer activities of this drug in cancer cells in culture and in in vivo models (1)(2)(3)(4)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Metformin inhibits growth and induces apoptosis and other antineoplastic responses in multiple cancer cell lines, and this is accompanied by modulation of different pathways and genes.…”

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

“…In mammals, metformin is generally believed to act through the activation of AMPK, one of the main regulators of cellular energy homeostasis (2,(14)(15)(16), but recent research suggests the existence of AMPK-independent mechanisms as well (17,18). More upstream, metformin is thought to activate AMPK through partial inhibition of complex I of the electron transport chain (ETC) and a resultant increase in the AMP/ATP ratio (19)(20)(21), although again, not all data support this theory (16,22).…”