The importance of arachidonic acid (AA) and linoleic acid (LA) metabolism is supported by animal and human epidemiology studies that indicate that aspirin and other NSAIDs that inhibit Cox activity, reduce the incidence and mortality of colon cancer and reduce polyps in patients with familial polyposis. Experimental studies with rodents indicate that NSAIDs reduce both the size and number of colon tumors induced by carcinogens. Prostaglandins and other lipids play a major role in the development and progression of colon and other cancers but the mechanism is not clear. The expression of Cox and LOX and NSAID treatment is linked to altered apoptosis, cell growth, cell differentiation and angiogenesis. We are examining arachidonic acid and linoleic acid metabolism, and the expression of Cox-1 and -2, and lipoxygenases in human cell lines. In addition to Cox-2, the expression of 15-lipoxygenase is higher in colorectal and prostate tumors. Data support the hypothesis that histone acetylation regulates the expression of 15-lipoxygenase-1 in human intestinal epithelial cells. In prostate cells 15-LOX-1 has a pro-tumorigenic effect while in colorectal tissue the lipoxygenase has an anti-tumorigenic effect. These lipoxygenases and their metabolites alter growth factor signaling pathways and 15-HETE and 13-HODE, the metabolites of AA and LA have opposing biological responses. In addition, the laboratory is studying the expression and regulation of Cox-1 and Cox-2 in cells. One unexpected finding is the up-regulation of Cox-1 but not 15-LOX-1 by HDAC inhibitors in brain cells. Our plans are to continue to investigate the regulation of 15-LOX and Cox-1 &-2 and to focus on how these enzyme contribute to the development of cancers.
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