title: 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(-/-) 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.
authors.affiliation: Cellular and Molecular Physiopathology of Obesity and Diabetes and Cell Death, Differentiation and Cancer Teams, INSERM U895, C3M, University of Nice Sophia-Antipolis, Faculty of Medicine, Nice, France.
authors.forename: Isaam
authors.initials: I
authors.lastname: Ben Sahra
authors.forename: Claire
authors.initials: C
authors.lastname: Regazzetti
authors.forename: Guillaume
authors.initials: G
authors.lastname: Robert
authors.forename: Kathiane
authors.initials: K
authors.lastname: Laurent
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Marchand-Brustel
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanti
authors.forename: Sophie
authors.initials: S
authors.lastname: Giorgetti-Peraldi
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bost
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C469991:DDIT4 protein, human; C469992:Ddit4 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases