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.

人类群体研究和实验动物模型表明，脂肪酸饱和度可能是一个关键， 前列腺癌的发生是由前列腺癌的发生发展所决定的。的 拟议的研究涉及细胞水平上的机制，这些机制可能解释了所报道的 n-3和n-6多不饱和脂肪酸（PUFA）。主要焦点是细胞表面蛋白聚糖（PGly）， 肿瘤发生潜力的重要介质。总的假设是，PGly代谢代表了一个水平， 调节饮食脂肪酸修饰的前列腺上皮细胞的致瘤潜力。 具体的假设是，n-3 PUFA增强PGly，syndecan 1的表达，并且这种调节 是由过氧化物酶体增殖物受体（PPAR）γ转录途径介导的。随而增加 多配体蛋白聚糖1通过抑制细胞生长和降低它们的侵袭性来抑制细胞的致瘤潜力。 特性.研究的一个独特之处是使用低密度脂蛋白（LDL）和LDL受体 将脂肪酸传递到细胞的途径。这一途径可能是一个主要的途径，提供脂肪 酸在体内，特别是前列腺癌细胞，其LDL受体缺乏反馈调节。LDL将 从非洲绿色猴子中获得，这些猴子喂食的膳食脂肪被认为对人类前列腺有相反的作用 癌症：n-6 PUFA（肿瘤促进）和n-3 PUFA（肿瘤抑制）。提出了四个具体目标。在Aim中 1、LDL生化特性及脂肪酸组成将被测定。研究将比较 通过LDL和非LDL受体依赖性途径将脂肪酸递送至细胞膜。在目标2中， 重点将是确定n-3 PUFA对细胞表面PGly、多配体蛋白聚糖1的影响。利用生物化学， 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syndecan合成，结构和基因的影响 调控此外，将在Pten+/-和Ren -/-的前列腺组织中研究对多配体蛋白聚糖1的体内作用。 喂食n-3或n-6 PUFA富集饮食的小鼠。在目标3中，研究将调查PPARy参与 多配体蛋白聚糖1的n-3 PUFA调节中的转录途径。在目标4中，研究将确定n-3 PUFA诱导的多配体蛋白聚糖1的变化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 前列腺癌生存率