The Sphingolipid Pathway in Colon Cancer Chemoprevention

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The long-term goal of this project is to define the role of sphingolipid pathway in colon carcinogenesis and to establish elements of this pathway as novel targets for effective colon cancer chemoprevention. Colorectal cancer is the 2nd leading cause of cancer-related deaths in the US; thus, identification of novel, effective pharmacological cancer-prevention strategies is essential. Accumulating evidence suggests that dietary factors, especially fat (lipids), are important in colon carcinogenesis. Bioactive sphingolipids may be key in regulating the prostanoid pathway of inflammation, significant in colon cancer pathogenesis. Sphingolipid metabolites such as ceramide, sphingosine, and sphingosine 1-phosphate (S1P) are a new class of lipid messengers that regulate cell proliferation, differentiation, and survival. Sphingosine kinase 1 (SK1), the enzyme that phosphorylates sphingosine to form S1P, is a critical regulator of sphingolipid-mediated functions, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro- apoptotic ceramide and sphingosine. Our laboratory found that SK1 and S1P mediate cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production in response to cytokines, and that SK1 downregulation by RNA interfering (RNAi) inhibits COX-2 expression and PGE2 production induced by cytokines, and S1P stimulates COX-2 expression and PGE2 production in HT-29, human colon cancer cells. SK1 overexpression in rat intestinal epithelial cells increases COX-2 expression. It is noteworthy that SK1 is upregulated in human colon tumors including adenomas and adenocarcinomas. We recently demonstrated that SK1 deficiency significantly reduces colon tumors including preneoplastic lesions, adenomas and cancers induced by azoxymethane (AOM), an established colon carcinogen in rodents. Based on these preliminary data, we hypothesize that the SK1/S1P pathway may play a pivotal role in colon carcinogenesis and constitute a novel target for chemoprevention against colon cancer. To investigate this concept, we propose the following Specific Aims: 1) Assess the role of the SK1/S1P pathway in colon carcinogenesis; 2) Determine the role and mechanism of the SK1/S1P pathway in regulating COX-2 expression; and 3) Assess the advantages of inhibition of the SK1/S1P pathway in colon cancer chemoprevention. The results obtained from this project will provide important insights into the role of the SK1/S1P pathway in colon carcinogenesis and identify novel targets for mechanism-based colon cancer chemoprevention, leading to future translational research exploiting the SK1/S1P pathway in colon carcinogenesis.