title: Distinct perturbation of the translatome by the antidiabetic drug metformin.
abstract: Metformin has been reported to lower cancer incidence among type II diabetics. Metformin exhibits antiproliferative and antineoplastic effects associated with inhibition of mammalian target of rapamycin complex 1 (mTORC1), but the mechanisms are poorly understood. We provide a unique genome-wide analysis of translational targets of canonical mTOR inhibitors (rapamycin and PP242) compared with metformin, revealing that metformin controls gene expression at the level of mRNA translation to an extent comparable to that of canonical mTOR inhibitors. Importantly, metformin's antiproliferative activity can be explained by selective translational suppression of mRNAs encoding cell-cycle regulators via the mTORC1/eukaryotic translation initiation factor 4E-binding protein pathway. Thus, metformin selectively inhibits translation of mRNAs encoding proteins that promote neoplastic proliferation, which should facilitate studies on metformin and related biguanides in cancer prevention and treatment.
authors.affiliation: Department of Oncology-Pathology,  Karolinska Institute, Stockholm 171 76,  Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morita
authors.forename: Ivan
authors.initials: I
authors.lastname: Topisirovic
authors.forename: Tommy
authors.initials: T
authors.lastname: Alain
authors.forename: Marie-Jose
authors.initials: MJ
authors.lastname: Blouin
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D046228:Microarray Analysis; D009369:Neoplasms / Q000188:drug therapy* / Q000517:prevention & control; D014176:Protein Biosynthesis / Q000187:drug effects*; D011687:Purines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011687:Purines; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D020123:Sirolimus