title: Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling.
abstract: We have shown before that constitutive DNA damage signaling represented by H2AX-Ser139 phosphorylation and ATM activation in untreated normal and tumor cells is a reporter of the persistent DNA replication stress induced by endogenous oxidants, the by-products of aerobic respiration. In the present study we observed that exposure of normal mitogenically stimulated lymphocytes or tumor cell lines A549, TK6 and A431 to metformin, the specific activator of 5'AMP-activated protein kinase (AMPK) and an inhibitor of mTOR signaling, resulted in attenuation of constitutive H2AX phosphorylation and ATM activation. The effects were metformin-concentration dependent and seen even at the pharmacologically pertinent 0.1 mM drug concentration. The data also show that intracellular levels of endogenous reactive oxidants able to oxidize 2',7'-dihydro-dichlorofluorescein diacetate was reduced in metformin-treated cells. Since persistent constitutive DNA replication stress, particularly when paralleled by mTOR signaling, is considered to be the major cause of aging, the present findings are consistent with the notion that metformin, by reducing both DNA replication stress and mTOR-signaling, slows down aging and/or cell senescence processes.
authors: Brander Cancer Research Institute and Department of Pathology, New York Medical College, Valhalla, NY 10595, USA.
authors: H Dorota
authors: HD
authors: Halicka
authors: Hong
authors: H
authors: Zhao
authors: Jiangwei
authors: J
authors: Li
authors: Frank
authors: F
authors: Traganos
authors: Sufang
authors: S
authors: Zhang
authors: Marietta
authors: M
authors: Lee
authors: Zbigniew
authors: Z
authors: Darzynkiewicz
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D016678:Genome; D006657:Histones / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D007004:Hypoglycemic Agents; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D004247:DNA; D008687:Metformin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases