Journal Article

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis

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

2011

Overview

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) up-regulates 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 with MDL 72527 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Acetyltransferases - metabolism / Animal models / Animals / Bacterial Toxins - toxicity / Bacteroides fragilis / Bacteroides fragilis - drug effects / Bacteroides fragilis - physiology / Biological Sciences / Cancer / Carcinogenesis / Cell Line / Cell lines / Cell Proliferation - drug effects / chemoprevention / Colitis / Colitis - pathology / Colon / Colonic Neoplasms - complications / Colonic Neoplasms - microbiology / Colonic Neoplasms - pathology / Colorectal cancer / Colorectal carcinoma / colorectal neoplasms / Deoxyribonucleic acid / Disease Models, Animal / DNA / DNA Damage / Enzyme Induction - drug effects / Enzymes / Epithelial cells / Epithelial Cells - drug effects / Epithelial Cells - enzymology / Etiology / Gastrointestinal tract diseases / Gene expression / Gram-negative bacteria / Humans / Inflammation / Inflammation - complications / Inflammation - pathology / Intestine / Intestines - drug effects / Intestines - pathology / metabolism / Mice / Mice, Inbred C57BL / Neoplasia / Oxidases / Oxidoreductases Acting on CH-NH Group Donors - biosynthesis / Oxidoreductases Acting on CH-NH Group Donors - metabolism / Polyamine Oxidase / Polyamines / Polyamines - metabolism / Precancerous Conditions - microbiology / Precancerous Conditions - pathology / Putrescine - analogs & derivatives / Putrescine - pharmacology / Reactive oxygen species / Recombinant Proteins - toxicity / Risk factors / Rodents / Spermine / Toxins / Tumorigenesis