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.

人类种群研究和实验动物模型表明，脂肪酸饱和可能是 决定一种特定脂肪是促进还是抑制前列腺癌发展的因素。这个 拟议的研究解决了细胞水平上可能解释已报道的不同效应的机制 N-3和n-6多不饱和脂肪酸(PUFA)。主要的焦点是细胞表面蛋白多糖(PGly)AS 肿瘤发生潜能的重要介体。总体假设是PGly的新陈代谢代表了一种水平 由膳食脂肪酸修饰的前列腺癌上皮细胞致癌潜能的调节。 具体的假设是，n-3PUFA增强了PGly和Syndecan 1的表达，并且这种调节 是由过氧化体增殖物受体(PPAR)y转录途径介导的。由此导致的增加 Syndecan 1通过抑制细胞生长和降低其侵袭力来抑制细胞的致瘤潜能 属性。研究的一个独特特点是使用低密度脂蛋白(LDL)和低密度脂蛋白受体 将脂肪酸输送到细胞的途径。这一途径很可能是脂肪输送的主要途径。 体内的酸，特别是对其低密度脂蛋白受体缺乏反馈调节的前列腺癌细胞。低密度脂蛋白将是 从喂食脂肪的非洲绿猴身上获得的脂肪对人类前列腺有相反的影响 癌症：n-6PUFA(促肿瘤)和n-3PUFA(肿瘤抑制)。提出了四个具体目标。在AIM 将测定低密度脂蛋白的生化特性和脂肪酸组成。研究将比较 通过低密度脂蛋白和非低密度脂蛋白受体依赖途径将脂肪酸输送到细胞膜。在目标2中， 重点将确定n-3多不饱和脂肪酸对细胞表面PGly，syndecan 1的影响。 分子生物学和免疫学技术，研究将表征前列腺产生的Syndecan 1 然后检测n-3多不饱和脂肪酸对合成、结构和基因的影响 监管。此外，体内对Syndecan 1的影响将在Pten+/-和Ren-/-的前列腺组织中进行研究。 饲喂n-3或n-6多不饱和脂肪酸强化饲料的小鼠。在目标3中，研究将调查PPARy的参与 在n-3PUFA调节Syndecan 1中的转录途径。在目标4中，研究将确定n-3如何 多不饱和脂肪酸诱导的Syndecan 1的变化会影响细胞的生长和侵袭特性。数据将提供 关于摄入特定膳食脂肪可能影响新陈代谢机制的重要新信息 和前列腺癌细胞的行为，并为旨在增加 前列腺癌存活率。