Anti-cancer mechanisms of n-3 PUFA mediated by syndecan

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Human population studies and experimental animal models indicate that fatty acid saturation may be a key factor in determining whether a particular fat promotes or inhibits the development of prostate cancer. The proposed studies address mechanisms at the cellular level that may account for the reported divergent effects of the n-3 and n-6 polyunsaturated fatty acids (PUFA). The major focus is on cell surface proteoglycans (PGly) as important mediators of tumorigenic potential. The overall hypothesis is that PGly metabolism represents a level of regulation of the tumorigenic potential of prostate epithelial cells that is modified by dietary fatty acids. Specific hypotheses are that n-3 PUFA enhance the expression of the PGly, syndecan 1 and that this regulation is mediated by the peroxisome proliferator receptor (PPAR) y transcriptional pathway. The resulting increase in syndecan 1 inhibits the tumorigenic potential of the cells by inhibiting cell growth and decreasing their invasive properties. A unique feature of the studies is the use of low density lipoproteins (LDL) and the LDL receptor pathway to deliver fatty acids to the cells. This pathway is likely to represent a major route for delivery of fatty acids in vivo, especially to prostate cancer cells whose LDL receptors lack feedback regulation. LDL will be obtained from African green monkeys fed dietary fats proposed to have opposite effects in human prostate cancer: n-6 PUFA (tumor promoting) and n-3 PUFA (tumor inhibiting). Four Specific Aims are proposed. In Aim 1, LDL biochemical characteristics and fatty acid composition will be determined. Studies will compare the delivery of fatty acids to cell membranes by LDL and non LDL-receptor dependent pathways. In Aim 2, the emphasis will be to determine effects of n-3 PUFA on the cell surface PGly, syndecan 1. Using biochemical, molecular biologic and immunologic techniques, studies will characterize the syndecan 1 produced by prostate cancer cell lines and then examine the effects of n-3 PUFA on syndecan synthesis, structure and gene regulation. In addition, in vivo effects on syndecan 1 will be studied in prostate tissue of Pten+/- and Ren -/- mice fed n-3 or n-6 PUFA-enriched diets. In Aim 3, studies will investigate the involvement of the PPARy transcriptional pathway in the n-3 PUFA regulation of syndecan 1. In Aim 4, studies will determine how n-3 PUFA-induced changes in syndecan 1 affect growth and invasive properties of the cells. Data will provide important new information on mechanisms by which intake of specific dietary fats may affect the metabolism and behavior of prostate cancer cells and provide rationale for dietary modifications aimed at increasing prostate cancer survival.