EICOSANOIDS AND INTESTINAL EPITHELIAL GROWTH

Vanderbilt University, Nashville TN

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Abstract

Colorectal cancer is the second leading cause of cancer deaths in the U.S. Last year at least 3.0 billion dollars was spent for hospitalization costs to care for patients diagnosed with colorectal cancer. Thus, colorectal cancer is a major health concern and its prevention or control should result in a significant saving of lives and health care dollars. Several studies have reported a 40-50 percent reduction in the risk of developing colorectal cancer in persons who take NSAIDs (like aspirin) on a regular basis. Even though NSAIDs are reported to have non-cyclooxygenase effects, one possible mechanism for a chemoprotective effect is via inhibition of cyclooxygenase enzymes. Two isoforms of this enzyme have been reported, which will be referred to as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in this proposal. COX-2 expression is markedly increased in 85-90 percent of human colorectal adenocarcinomas, while COX-1 levels remain unchanged. Rodents treated with the carcinogen, azoxymethane (AOM), develop numerous intestinal tumors. Several studies have shown a significant reduction in tumor size and burden in AOM-treated rats with a wide variety of NSAIDs. COX-2 levels are increased in 100 percent of the tumors that develop following administration of AOM to rats. Min mice have a germline mutation in the murine homolog of the adenomatous polyposis coli (mAPC) gene and develop multiple intestinal tumors. Adenomas which develop in Min mice express high levels of COX-2 and their tumor multiplicity is reduced 90 percent following NSAID treatment. APCdelta716 mice develop hundreds of tumors per intestine which, like the min mouse, express high levels of COX-2, compared with adjacent normal mucosa. When APCdelta716 mice were bred with COX-2 null mice there was a 80-90 percent reduction in tumor multiplicity in the homozygous COX-2 null offspring. These results indicate that COX-2 plays some role in intestinal carcinogenesis. The goals of the current proposal are to determine the mechanisms by which COX-2 expression is elevated in human colorectal cancer cells and to investigate the downstream effects of eicosanoids generated via the cyclooxygenase pathway. The specific aims include: 1) Determination of the downstream effects of prostaglandins and the mechanisms by which they regulate proliferation and apoptosis in intestinal cells. 2) Evaluate the trans-acting factors which lead to constitutive expression of COX-2 in human colon cancer cells. 3) Characterize two genes (X-7 and X-18) which lead to upregulation of COX-2 expression when they are somatically mutated in RIE-1 cells.