The importance of arachidonic acid and linoleic acid metabolism is supported by animal and human epidemiology studies that indicate that aspirin and other NSAIDs 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. Recent studies reported that Cox-2 is significantly expressed in colon and other tumors compared to neighboring normal tissue. 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 these enzymes and NSAID treatment is linked to altered apoptosis, cell growth, cell differentiation and angiogenesis. We are examining arachidonic and linoleic acid metabolism, and the expression of Cox-1 and -2, and lipoxygenases in human cell lines. Butyrate-induced differentiation and apoptosis several human colon cells and resulted in a decrease Cox-2 expression and the increased expression of 15-lipoxygenase. A dramatic shift from prostaglandins metabolites to lipoxygenase metabolites was observed. Butyrate also induces apoptosis, but the addition of Cox inhibitors did not alter the apoptosis in these cells. However, the addition of a lipoxygenase inhibitor enhanced apoptosis induced by butyrate which suggest that 15-lipoxygenase acts to attenuate apoptosis. Expression of 15-lipoxygenase was observed in human colon tissue with a 2-3 fold increase in expression in colorectal tumors. The 15-lipoxygenase was localized in the intestinal epithelial cell. Data support the hypothesis that histone acetylation regulates the expression of 15-lipoxygenase-1 in human intestinal epithelial cells. We are currently studying the regulation of 15-lipoxygenase in human colorectal and brain cells in culture. We are also developing model systems for examining the biological effects of Cox-1/-2 and 15-lipoxygenase over-expression.
Showing the most recent 10 out of 29 publications
