The role of spermine oxidase in inflammation-associated carcinogenesis

Polyamines are ubiquitous cationic molecules that are essential for cell growth and function in numerous cellular processes. Polyamine metabolic pathways have been demonstrated to be dysregulated in cancers and other diseases and as such have been recognized as therapeutic targets. Chronic inflammation is estimated to contribute to the development of 20-30% of all epithelial cancers, though the molecular links remain to be clarified. The recently described spermine oxidase (SMO) catalyzes the back-conversion of spermine to spermidine, hydrogen peroxide, and 3-aminopropanal. SMO is rapidly induced by multiple inflammatory stimuli including Helicobacter pylori and cytokines, leading to the production of reactive oxygen species (ROS) and DNA damage. Studies utilizing human tissue microarrays demonstrate that median SMO immunohistochemical staining intensity was 53% higher in benign prostatic tissue from men with prostate cancer vs normal controls (p<0.0001, U test). Further, compared to adjacent benign tissues, SMO levels in prostatic intraepithelial neoplasia and adenocarcinoma tissues were significantly elevated (37% and 17% higher; p<0.01 and p<0.05, respectively, paired t-tests). Enterotoxigenic Bacteroides fragilis (ETBF) induces SMO-dependent DNA damage in intestinal epithelial cell lines. In addition, SMO is upregulated and the polyamine oxidase inhibitor MDL 72,527 reduces inflammation and proliferation in murine models of ETBF-induced colitis. Finally, MDL 72,527 treatment resulted in a 69% decrease in colon tumorigenesis in ETBF-infected APC-deficient Multiple Intestinal Neoplasia (Min) mice (p<0.001, U-test). These results indicate that SMO contributes to inflammation-associated carcinogenesis through production of ROS and therefore represents a novel chemopreventive or chemotherapeutic target.