Acidic pH induces topoisomerase II-mediated DNA damage

Hai Xiao, Tsai Kun Li, Jin Ming Yang, Leroy F. Liu

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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-β-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.

Original languageEnglish (US)
Pages (from-to)5205-5210
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number9
DOIs
StatePublished - Apr 29 2003

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Type II DNA Topoisomerase
DNA Damage
Ataxia Telangiectasia
Poisons
Carcinogenesis
9,10-Dimethyl-1,2-benzanthracene
Hypoxanthine
DNA Breaks
Barrett Esophagus
Glucosides
Etoposide
Mutation Rate
Transferases
Neoplasms
Phosphotransferases
Up-Regulation
Animal Models
Phosphorylation

All Science Journal Classification (ASJC) codes

  • General

Cite this

Xiao, Hai ; Li, Tsai Kun ; Yang, Jin Ming ; Liu, Leroy F. / Acidic pH induces topoisomerase II-mediated DNA damage. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 9. pp. 5205-5210.
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Acidic pH induces topoisomerase II-mediated DNA damage. / Xiao, Hai; Li, Tsai Kun; Yang, Jin Ming; Liu, Leroy F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 9, 29.04.2003, p. 5205-5210.

Research output: Contribution to journalArticle

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