Anti-cancer mechanisms of n-3 PUFA mediated by syndecan 1

Wake Forest University Health Sciences, Winston-Salem NC

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Abstract

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