Omega-3 PUFA-gene interaction in prostate cancer

描述（由申请人提供）：我们之前的研究表明，I3 PUFA可以降低前列腺癌（PCa）的生长，减缓组织病理进展，提高生存率，而I6 PUFA具有相反的效果。为了系统地评估PCa中加氧酶和PUFAs之间的相互作用，我们在前列腺特异性pten缺失小鼠中敲除了Cox1、Cox2、Lox5、Lox12和Lox15。我们的研究结果表明，PCa中存在复杂的pufa -基因相互作用：(a) Cox1的缺失以pufa依赖的方式对PCa的生长有显著影响；即，I6组Cox1基因敲除小鼠的肿瘤生长明显减弱，而I3组小鼠的肿瘤生长则增加。换句话说，I3 PUFA的保护作用需要Cox1，这表明Cox1的I3代谢物（如PGE3）参与其中。另一方面，Cox1的I6代谢产物（如PGE2）在肿瘤形成中起促进作用。(b) Cox2的缺失降低了I6和I3日粮中PCa的生长。因此，Cox2的I6代谢产物促进肿瘤生长，I3 PUFA的抑制作用不依赖于Cox2。(c) Lox5的缺失降低了I6日粮中PCa的生长，但对I3日粮没有影响，说明I6中Lox5的代谢物（如LTB4）促进肿瘤生长，I3 PUFA的保护作用不依赖于Lox5。(d) Lox12或Lox15的缺失不影响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Cox1代谢，I3 PUFA的抗增殖作用部分是由Cox1代谢物介导的。此外，I6 PUFA被Cox1、Cox2和Lox5代谢，相应的代谢物在刺激PCa生长中起重要作用。为了验证我们的假设，我们提出了三个特定的目标：(1)研究PUFA-基因相互作用对PCa生长的细胞机制；(2)鉴定在PCa中重要的I3和I6 PUFA的代谢物；(3)研究代谢物信号在PCa细胞增殖和凋亡中的作用。

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.