title: Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation.
abstract: We show that the antidiabetic drug metformin inhibits the expression of genes coding for multiple inflammatory cytokines seen during cellular senescence. Conditioned medium (CM) from senescent cells stimulates the growth of prostate cancer cells but treatment of senescent cells with metformin inhibited this effect. Bioinformatic analysis of genes downregulated by metformin suggests that the drug blocks the activity of the transcription factor NF-κB. In agreement, metformin prevented the translocation of NF-κB to the nucleus and inhibited the phosphorylation of IκB and IKKα/β, events required for activation of the NF-κB pathway. These effects were not dependent on AMPK activation or on the context of cellular senescence, as metformin inhibited the NF-κB pathway stimulated by lipopolysaccharide (LPS) in ampk null fibroblasts and in macrophages. Taken together, our results provide a novel mechanism for the antiaging and antineoplastic effects of metformin reported in animal models and in diabetic patients taking this drug.
authors.affiliation: Département de Biochimie, Université de Montréal, Pavillon Roger-Gaudry 2900 boul. Édouard Montpetit, Montréal, QC, H3C 3J7, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Moiseeva
authors.forename: Xavier
authors.initials: X
authors.lastname: Deschênes-Simard
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: St-Germain
authors.forename: Sebastian
authors.initials: S
authors.lastname: Igelmann
authors.forename: Geneviève
authors.initials: G
authors.lastname: Huot
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Cadar
authors.forename: Véronique
authors.initials: V
authors.lastname: Bourdeau
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferbeyre
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D008687:Metformin; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases