Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1.
By I. Ben-Sahra, Claire Regazzetti, G. Robert, K. Laurent, Y. Le Marchand-Brustel, P. Auberger, J. Tanti, S. Giorgetti-Peraldi, F. Bost. Cancer Research, 2011
610 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/565e7e6c0bf18d5ebc013f562a65935b8e29132c
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In Molecular Biology
Citations in the corpus
- Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality. (2015, background): “Metformin has been shown to inhibit mTOR by increasing expression of REDD1, a p53 target in a manner dependent on p53 (17).”