Acidic pH induces topoisomerase II-mediated DNA damage

• DOI: 10.1073/pnas.0935978100
• Publication Date: 2003-04-29T16:23:56Z
• Authors: Hai Xiao; Tsai-Kun Li; Jin-Ming Yang; Leroy F. Liu
• Keywords: 0301 basic medicine; 9,10-Dimethyl-1,2-benzanthracene; Diketopiperazines; Hydrogen-Ion Concentration; Catalysis; Piperazines; Up-Regulation; Histones; Mice; 03 medical and health sciences; DNA Topoisomerases, Type II; Mutagenesis; Carcinogens; Serine; Tumor Cells, Cultured; Animals; Humans; Female; Phosphorylation; Tumor Suppressor Protein p53; Acids; DNA Damage

Acidic pH plays an important role in various pathophysiological states and has been demonstrated to be carcinogenic animal models. Recent studies have also implicated acidic the development of preneoplastic Barrett's esophagus human. However, little is known about molecular mechanism underlying pH-induced carcinogenesis. In current study, we show that pH, like topoisomerase II (TOP2) poison VP-16 (demethylepipodophyllotoxin ethylidene-β- d -glucoside), induces tumors 9,10-dimethyl-1,2-benzanthracene(DMBA)-initiated mice. The following tissue culture models suggested acts a TOP2 induce TOP2-mediated DNA damage: ( i ) TOP2-dependent damage signals as evidenced by up-regulation p53 Ser-139 phosphorylation H2AX [a substrate for ataxia telangiectasia mutated (ATM)/ATM Rad3-related (ATR) kinases]; ii cytotoxicity tumor cells reduced TOP2-deficient cells; iii increases mutation frequency hypoxanthine phosphoribosyl transferase (HPRT) gene manner; iv reversible strand breaks vitro . We discuss possibility may contribute