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

Syndecan介导的n-3 PUFA抗癌机制

• 批准号: 7152260
• 负责人: YONG Q CHEN
• 金额: $ 10.14万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152260
• 关键词: Cercopithecidae; apoptosis; cancer prevention; cell line; cellular oncology; chemoprevention; dietary lipid; dietary supplements; genetic regulation; genetic transcription; genotype; laboratory mouse; low density lipoprotein; low density lipoprotein receptor; marine animal oil; neoplastic cell; nutrition aspect of cancer; nutrition related tag; omega 3 fatty acid; peroxisome proliferator activated receptor; prostate neoplasms; syndecan

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.

人口研究和实验动物模型表明脂肪酸饱和可能是关键 确定特定脂肪是否促进或抑制前列腺癌的发展的因素。这 拟议的研究解决了细胞水平的机制，这可能解释了报道的不同 N-3和N-6多不饱和脂肪酸（PUFA）。主要重点是用于细胞表面蛋白聚糖（pgly） 致癌潜力的重要介体。总体假设是PGLY代谢代表一个水平 由饮食脂肪酸修饰的前列腺上皮细胞的致瘤潜力调节。 特定的假设是N-3 PUFA增强了PGLY的表达，Syndecan 1，并且该调节 由过氧化物酶体增殖物受体（PPAR）Y转录途径介导。由此产生的增加 Syndecan 1通过抑制细胞生长并降低其侵入性，抑制细胞的致瘤潜力 特性。研究的独特特征是使用低密度脂蛋白（LDL）和LDL受体 向细胞输送脂肪酸的途径。该途径可能代表了脂肪交付的主要途径 体内酸，特别是对于LDL受体缺乏反馈调节的前列腺癌细胞。 LDL会 从喂食饮食脂肪的非洲绿猴中获得的，提议在人类前列腺中产生相反的影响 癌症：N-6 PUFA（促进肿瘤）和N-3 PUFA（抑制肿瘤）。提出了四个具体目标。目标 1，LDL生化特征和脂肪酸组成将被确定。研究将比较 LDL和非LDL受体依赖途径将脂肪酸递送至细胞膜。在AIM 2中 重点是确定N-3 PUFA对细胞表面PGLY的影响，Syndecan 1。使用生化， 分子生物学和免疫学技术，研究将表征前列腺产生的syndecan 1 癌细胞系，然后检查N-3 PUFA对联合合成，结构和基因的影响 规定。此外，将在PTEN +/-和REN的前列腺组织中研究体内对Syndecan 1的影响 - / - 喂养N-3或N-6富含PUFA的饮食的小鼠。在AIM 3中，研究将研究PPARY的参与 n-3 PUFA调节syndecan 1中的转录途径。在AIM 4中，研究将决定N-3如何 PUFA诱导的Syndecan 1的变化会影响细胞的生长和侵入性。数据将提供 有关特定饮食脂肪摄入可能影响新陈代谢的机制的重要新信息 和前列腺癌细胞的行为，并为旨在增加的饮食修饰提供理由 前列腺癌存活。