Acidic pH induces topoisomerase II-mediated DNA damage.
Acidic pH plays an important role in various pathophysiological states and has been demonstrated to be carcinogenic in animal models. Recent studies have also implicated acidic pH in the development of preneoplastic Barrett's esophagus in human. However, little is known about the molecular mechanism underlying acidic pH-induced carcinogenesis. In the current study, we show that acidic pH, like the topoisomerase II (TOP2) poison VP-16 (demethylepipodophyllotoxin ethylidene-beta-D-glucoside), induces tumors in 9,10-dimethyl-1,2-benzanthracene(DMBA)-initiated mice. The following studies in tissue culture models have suggested that acidic pH acts like a TOP2 poison to induce TOP2-mediated DNA damage: (i) acidic pH induces TOP2-dependent DNA damage signals as evidenced by up-regulation of p53 and Ser-139 phosphorylation of H2AX [a substrate for ataxia telangiectasia mutated (ATM)ATM and Rad3-related (ATR) kinases]; (ii) acidic pH-induced cytotoxicity in tumor cells is reduced in TOP2-deficient cells; (iii) acidic pH increases the mutation frequency of the hypoxanthine phosphoribosyl transferase (HPRT) gene in a TOP2-dependent manner; and (iv) acidic pH induces reversible TOP2-mediated DNA strand breaks in vitro. We discuss the possibility that TOP2-mediated DNA damage may contribute to acidic pH-induced carcinogenesis.
Xiao
Hai
H
Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635, USA.
Li
Tsai-Kun
TK
Yang
Jin-Ming
JM
Liu
Leroy F
LF
D015127:9,10-Dimethyl-1,2-benzanthracene; D000143:Acids / Q000737:chemistry*; D000818:Animals; D002273:Carcinogens; D002384:Catalysis; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D054659:Diketopiperazines; D005260:Female; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D016296:Mutagenesis; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
D000143:Acids; D002273:Carcinogens; D054659:Diketopiperazines; D006657:Histones; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D012694:Serine; D015127:9,10-Dimethyl-1,2-benzanthracene; D004250:DNA Topoisomerases, Type II