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: 8434839
• 负责人: YONG Q CHEN
• 金额: $ 33.56万
• 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/8434839
• 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; caspase-3; desaturase; gene interaction; human disease; in vivo; infancy; mortality; prostaglandin E3; prostaglandin EP2 receptor; prostate cancer cell; 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.

描述（由申请人提供）：我们以前已经表明，I3 PUFA减少前列腺癌（PCa）的生长，减缓组织病理学进展和增加生存率，而I6 PUFA具有相反的效果。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Cox 1、Cox 2、Lox 5、Lox 12和Lox 15。我们的研究结果表明，PCa中存在复杂的PUFA-基因相互作用：（a）Cox 1的缺失以PUFA依赖性方式对PCa生长产生显著影响;即，在I6饮食的Cox 1敲除小鼠中，肿瘤生长显著减少，而在I3饮食的小鼠中，肿瘤生长增加。换句话说，I3 PUFA的保护作用需要Cox 1，这表明Cox 1的I3代谢物（例如PGE 3）参与其中。另一方面，Cox 1的I6代谢产物（如PGE 2）对肿瘤形成起促进作用。(b)I6和I3饮食中Cox 2的缺失降低了PCa的生长。因此，Cox 2的I6代谢产物促进肿瘤生长，I3 PUFA的抑制作用不依赖于Cox 2。(c)Lox 5的缺失降低了I6饮食中PCa的生长，但对I3饮食没有影响，这表明Lox 5的I6代谢产物（例如LTB 4）促进肿瘤生长，并且I3 PUFA的保护作用不依赖于Lox 5。(d)Lox 12或Lox 15的缺失并不影响PCa的生长，这表明在我们的模型中，这两种酶对PCa并不重要。我们假设I3 PUFA在体内主要由Cox 1代谢，I3 PUFA的抗增殖作用部分由Cox 1代谢产物介导。另外，I6 PUFA主要由Cox 1、Cox 2和Lox 5代谢，其代谢产物在促进PCa生长中起重要作用。为了验证我们的假设，提出了三个具体的目标：（1）研究PUFA-基因相互作用对PCa生长的细胞机制，（2）鉴定PCa中重要的I3和I6 PUFA代谢产物，（3）检测PCa细胞增殖和凋亡中的代谢产物信号。