Omega-3 PUFA-gene interaction in prostate cancer

Omega-3 PUFA 与前列腺癌中基因的相互作用

基本信息

批准号：
8607164
负责人：
YONG Q CHEN
金额：
$ 34.63万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/8607164
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

项目摘要

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）：我们先前表明i3 PUFA降低了前列腺癌（PCA）的生长，组织病理学进展减慢并增加生存率，而I6 PUFA的影响相反。为了系统地评估PCA中的氧合酶与PUFA之间的相互作用，我们在前列腺特异性PTEN-NULL小鼠中淘汰了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的损失对PCA的生长以PUFA依赖性方式具有重大影响；也就是说，在i6饮食上COX1敲除小鼠中，肿瘤的生长显着降低，而I3饮食中小鼠的肿瘤生长增加。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）涉及。另一方面，COX1的I6代谢产物（例如PGE2）在肿瘤形成中起促进作用。（b）COX2损失降低了i6和i3饮食的PCA生长。因此，COX2的I6代谢产物促进肿瘤的生长，而I3 PUFA的抑制作用不依赖于COX2。（c）LOX5的损失降低了i6饮食的PCA生长，但对i3饮食没有影响，这表明LOX5（例如LTB4）的i6代谢产物促进肿瘤的生长，而i3 PUFA的保护作用与LOX5无关。（d）LOX12或LOX15的损失不影响PCA的生长，这表明这两种酶对我们的模型中的PCA并不重要。我们假设I3 PUFA主要由Cox1在体内代谢，并且i3 PUFA的抗增殖作用部分是由Cox1代谢物（S）介导的。此外，I6 PUFA由COX1，COX2和LOX5代谢，相应的代谢产物在刺激PCA生长中起着重要作用。为了检验我们的假设，提出了三个具体目的：（1）研究PCA生长的PUFA-GENE相互作用的细胞机制，（2）（2）鉴定PCA中I3和I6 PUFA的代谢物（S）在PCA中很重要，并且（3）检查PCA细胞增殖和凋亡中PCA细胞增殖中的代谢物信号传导。