Omega-3 PUFA-gene interaction in prostate cancer

Omega-3 PUFA 与前列腺癌中基因的相互作用

• 批准号: 8215565
• 负责人: YONG Q CHEN
• 金额: $ 35.7万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215565
• 关键词: Affect; Angiogenic Factor; Animal Model; Apoptosis; Attention; CD19 gene; CD3 Antigens; Cardiovascular Diseases; Cell Death; Cell Line; Cell Proliferation; Cells; Cholesterol; Cleaved cell; Complex; Development; Diet; Dietary Fats; Dinoprostone; Disease; EP4 receptor; Eicosanoids; Environmental Risk Factor; Enzymes; Essential Fatty Acids; Fatty Acids; Fatty acid glycerol esters; Gene Expression; Genes; Genotype; Growth; Health; Histopathology; Human; Immunohistochemistry; Inflammation; Knock-out; Knockout Mice; Lead; Leukotriene B4; Lipoxygenase; Malignant Neoplasms; Malignant neoplasm of prostate; Mammals; Mediating; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Omega-3 Fatty Acids; Oxygenases; Phenotype; Play; Polyunsaturated Fatty Acids; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostate; Relative (related person); Reporting; Role; Signal Transduction; Testing; Tissues; Wild Type Mouse; angiogenesis; cancer cell; caspase-3; desaturase; gene interaction; human disease; in vivo; infancy; mortality; prostaglandin E3; prostaglandin EP2 receptor; protective effect; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): We have previously shown that I3 PUFA reduced prostate cancer (PCa) growth, slowed histopathological progression and increased survival, whereas I6 PUFA had the opposite effects. To systematically assess the interaction between oxygenases and PUFAs in PCa, we knocked out Cox1, Cox2, Lox5, Lox12, and Lox15 in prostate-specific Pten-null mice. Our results indicate a complex PUFA-gene interaction in PCa: (a) Loss of Cox1 had significant effects on PCa growth in a PUFA-dependent manner; namely, tumor growth was significantly diminished in Cox1 knockout mice on I6 diet, whereas it increased in mice on I3 diet. In other words, Cox1 was required for the protective effects of I3 PUFA, suggesting that I3 metabolites of Cox1 (e.g. PGE3) are involved. On the other hand, I6 metabolites of Cox1 (e.g. PGE2) play a promoting role on tumor formation. (b) Loss of Cox2 reduced PCa growth on both I6 and I3 diet. Therefore, I6 metabolites of Cox2 promote tumor growth, and suppressive effects of I3 PUFA do not depend upon Cox2. (c) Loss of Lox5 reduced PCa growth on I6 diet but had no effect on I3 diet, suggesting that I6 metabolites of Lox5 (e.g. LTB4) promote tumor growth, and protective effects of I3 PUFA are independent of Lox5. (d) Loss of Lox12 or Lox15 did not affect PCa growth, suggesting that these two enzymes are not critical for PCa in our model. We hypothesize that I3 PUFA is primarily metabolized by Cox1 in vivo and that the anti-proliferative effect of I3 PUFA is, in part, mediated by Cox1 metabolite(s). Furthermore, I6 PUFA is metabolized by Cox1, Cox2 and Lox5, and the corresponding metabolites play important roles in stimulating PCa growth. To test our hypothesis, three specific aims are proposed: (1) Study the cellular mechanism(s) of PUFA-gene interaction on PCa growth, (2) Identify metabolite(s) of I3 and I6 PUFA important in PCa and (3) Examine metabolite signaling in PCa cell proliferation and apoptosis. PUBLIC HEALTH RELEVANCE: Cardiovascular disease, cancer, obesity and type 2 diabetes collectively are responsible for more than 80% of the disease-related mortality in the US. Dietary fat plays critical roles in each of these diseases. In cardiovascular disease, cholesterol is considered as one of the major culprits, and in obesity it is believed that a high fat diet is mainly responsible. However, how dietary fat contributes to cancer is less clear. We are largely ignorant on the relative amounts and the types of dietary fats that are either detrimental or beneficial for this disease. Our proposal will investigate the interaction between dietary polyunsaturated fatty acids and oxygenases, to determine the role of their metabolites in the inhibitory effect of omega-3 and stimulatory effect of omega-6 on prostate cancer.

描述（由申请人提供）：我们之前已经表明，I3 PUFA 可以减少前列腺癌（PCa）的生长，减缓组织病理学进展并增加存活率，而 I6 PUFA 则具有相反的作用。为了系统地评估 PCa 中加氧酶和 PUFA 之间的相互作用，我们在前列腺特异性 Pten 缺失小鼠中敲除 Cox1、Cox2、Lox5、Lox12 和 Lox15。我们的结果表明 PCa 中存在复杂的 PUFA-基因相互作用：(a) Cox1 的缺失以 PUFA 依赖性方式对 PCa 生长产生显着影响；也就是说，在采用 I6 饮食的 Cox1 敲除小鼠中，肿瘤生长显着减少，而在采用 I3 饮食的小鼠中，肿瘤生长则增加。换句话说，I3 PUFA 的保护作用需要 Cox1，这表明 Cox1 的 I3 代谢物（例如 PGE3）参与其中。另一方面，Cox1的I6代谢物（例如PGE2）对肿瘤的形成起到促进作用。 (b) Cox2 的缺失降低了 I6 和 I3 饮食中 PCa 的生长。因此，Cox2的I6代谢物促进肿瘤生长，而I3 PUFA的抑制作用不依赖于Cox2。 (c) Lox5 的缺失降低了 I6 饮食中 PCa 的生长，但对 I3 饮食没有影响，表明 Lox5 的 I6 代谢物（例如 LTB4）促进肿瘤生长，并且 I3 PUFA 的保护作用独立于 Lox5。 (d) Lox12 或 Lox15 的丢失不会影响 PCa 的生长，表明这两种酶在我们的模型中对 PCa 并不重要。我们假设 I3 PUFA 在体内主要由 Cox1 代谢，并且 I3 PUFA 的抗增殖作用部分是由 Cox1 代谢物介导的。此外，I6 PUFA由Cox1、Cox2和Lox5代谢，相应的代谢物在刺激PCa生长中发挥重要作用。为了检验我们的假设，提出了三个具体目标：（1）研究 PUFA 与基因相互作用对 PCa 生长的细胞机制，（2）鉴定在 PCa 中重要的 I3 和 I6 PUFA 代谢物，以及（3）检查 PCa 细胞增殖和凋亡中的代谢信号传导。 公共卫生相关性：心血管疾病、癌症、肥胖和 2 型糖尿病共同导致了美国 80% 以上的疾病相关死亡率。膳食脂肪在这些疾病中都起着至关重要的作用。在心血管疾病中，胆固醇被认为是罪魁祸首之一，而在肥胖中，人们认为高脂肪饮食是罪魁祸首。然而，膳食脂肪如何导致癌症尚不清楚。我们很大程度上不了解对这种疾病有害或有益的膳食脂肪的相对数量和类型。我们的提案将研究膳食多不饱和脂肪酸和加氧酶之间的相互作用，以确定它们的代谢物在 omega-3 的抑制作用和 omega-6 对前列腺癌的刺激作用中的作用。