Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis

Andrew C. Goodwin, Christina E. Destefano Shields, Shaoguang Wu, David L. Huso, Xin Qun Wu, Tracy R. Murray-Stewart, Amy Hacker-Prietz, Shervin Rabizadeh, Patrick M. Woster, Cynthia L. Sears, Robert A. Casero

Research output: Contribution to journalArticlepeer-review

Abstract

It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) upregulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N1,N4-bis(2,3- butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment withMDL72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention.

Original languageEnglish (US)
Pages (from-to)15354-15359
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number37
DOIs
StatePublished - Sep 13 2011

Keywords

  • Adenomatous polyposis coli
  • Inflammatory bowel diseases

ASJC Scopus subject areas

  • General

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