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.
Highlights
Metformin, a widely used antidiabetic drug, seems to reduce the incidence of cancer in diabetic patients [1] and inhibit cancer cell proliferation and tumor growth in animal models [2,3,4]
Effects of metformin on mTOR and cell growth are not mediated by AMPactivated protein kinase (AMPK) in prostate cancer cells [3]
Because of its role in mTOR regulation, we asked whether REDD1 could mediate metformin effects
Summary
A widely used antidiabetic drug, seems to reduce the incidence of cancer in diabetic patients [1] and inhibit cancer cell proliferation and tumor growth in animal models [2,3,4]. Metformin provokes cell-cycle arrest in G0–G1 but does not induce apoptosis or autophagy in prostate cancer cells [3]. Metformin regulates the AMPactivated protein kinase (AMPK)/mTOR pathway, as it activates AMPK [5] and inhibits the mTOR pathway via tuberous sclerosis 2 protein (TSC2). Because AMPK activation inhibits energy-consuming pathways and protein synthesis [6], metformin could inhibit cell proliferation through AMPK. We showed that downregulation of AMPK did not affect metformin action on prostate cancer cell growth and mTOR inhibition [3], suggesting a role for an alternative pathway. We show that REDD1 is regulated by p53 and is required for metformin effects on cell-cycle arrest. Our study highlights the p53/REDD1 axis as a novel molecular target of metformin
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