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, N(1),N(4)-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.