The overall objectives of this renewal are to test the hypothesis that production of reactive oxygen species through intracellular polyamine oxidation by our recently cloned spermine oxidase (SMO) plays a significant role in inflammation-associated tumorigenesis. It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation. Although many of the inflammatory cells, cytokines, and pathways have been implicated, the molecular events linking inflammation and the necessary carcinogenic DNA mutations are unknown. Our recently discovered human SMOmay provide one such link. SMO is a new member of the mammalian polyamine catabolic pathway. The products of its activity are the polyamine, spermidine, 3-aminopropanal, and the reactive oxygen species, H2O2. We have demonstrated that large, tumor-specific increases of spermine oxidase activity can lead to selective tumor cell death, thus providing a strategy for targeted antitumor therapy. However, chronic production of non-cytotoxic levels of H2O2 can have deleterious effects on normal cells, including oxidative DNA damage leading to mutations. We have recently discovered that SMO is induced in several epithelial cell typesby multiple stimuli including Helicobacter pylori infection, exposure to Enterotoxigenic Bacteroides fragilis (ETBF), and exposure to the general mediators of inflammation, TNF?, IL-1? IL-6, &IL8. Both H. pylori and B. fragilis are implicated in inflammation associated cancers, gastric and colon, respectively. The production, release,and activity of TNF? and other cytokines are common responses to inflammation and injury. The fact that these stimuli all lead to increased SMO expression, H2O2 production, and measurable DNA damage that is blocked by inhibition of SMO, suggest that ROS produced by the polyamine catabolic enzyme SMO is a direct mechanism linking inflammation and potentially carcinogenic DNA damage. Thus, these data indicate that SMO may represent a new and vitally important chemopreventive target. Therefore, to assess the potential of SMO as a target for chemopreventive therapy we will: 1) define the molecular mechanisms by which inflammatory stimuli induce the expression of SMO and produce DNA damage;2) use a B. fragilis APC+/-MinAPC?716 mouse model alone, and in combination with inhibitors of SMO and/or SMO knockout, to determine if a direct link exists between bacterialinflammation, SMO activity, ROS production and development of tumors. By understanding the pathways involved in regulating inflammation-induced SMO expression, H2O2 production, and DNA damage, and by defining their role in the initiation and progression of inflammation-associated epithelial cancers, it is likely that multiple new targets for chemopreventive therapy will emerge.
Inflammation is associated with the development of many epithelial cancers;however, the molecular basis of this association is not clearly understood. The results presented in this application implicate hydrogen peroxide produced by spermine oxidase (SMO) in response to TNF? and other mediators of inflammation, asa direct link between inflammation and potentially carcinogenic DNA damage. A better understanding of the role of SMO in inflammation-induced cancers should aid in treatment strategies to prevent cancer.
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