Omega-3 PUFA-gene interaction in prostate cancer

描述(申请人提供)：我们先前已经证明，I3PUFA可以减少前列腺癌(PCA)的生长，减缓组织病理进展和提高存活率，而I6PUFA具有相反的作用。为了系统地评估前列腺癌中加氧酶和多不饱和脂肪酸之间的相互作用，我们在前列腺特异性Pten缺失小鼠中敲除了Cox1、Cox2、Lox5、Lox12和Lox15。我们的结果表明在PCa中存在复杂的PUFA-基因相互作用：(A)Cox1基因的缺失以一种依赖于PUFA的方式显著影响PCa的生长；即，在I6饮食的Cox1基因敲除小鼠肿瘤生长显著减少，而在I3饮食的小鼠肿瘤生长显著增加。换句话说，I3多不饱和脂肪酸的保护作用需要Cox1，这表明Cox1的I3代谢物(如PGE3)参与了保护作用。另一方面，Cox1的I6代谢物(如PGE2)在肿瘤形成中起促进作用。(B)失去COX2降低了I6和I3饮食中的PCA生长。因此，COX2的I6代谢物促进肿瘤生长，而I3多不饱和脂肪酸的抑制作用不依赖于COX2。(C)Lox5的缺失减少了I6饮食中Pca的生长，但对I3饮食中的Pca生长无影响，提示Lox5的I6代谢产物(如LTB4)促进肿瘤生长，I3多不饱和脂肪酸的保护作用不依赖Lox5。(D)Lox12或Lox15的缺失不会影响PCa的生长，这表明在我们的模型中，这两种酶对PCa不是关键的。我们假设i3多不饱和脂肪酸在体内主要由Cox1代谢，其抗增殖作用部分是由Cox1代谢物(S)介导的。此外，I6多不饱和脂肪酸被Cox1、Cox2和Lox5代谢，相应的代谢产物在刺激PCA生长方面起着重要作用。为了验证我们的假设，我们提出了三个具体的目标：(1)研究多不饱和脂肪酸与基因相互作用对前列腺癌生长的细胞机制(S)；(2)确定I3和I6多不饱和脂肪酸在前列腺癌中的重要代谢物(S)；(3)研究代谢产物在前列腺癌细胞增殖和凋亡中的信号转导作用。 公共卫生相关性：心血管疾病、癌症、肥胖症和2型糖尿病合计占美国疾病相关死亡的80%以上。饮食中的脂肪在这些疾病中都起着关键作用。在心血管疾病中，胆固醇被认为是主要罪魁祸首之一，而在肥胖症中，高脂肪饮食被认为是主要原因。然而，饮食脂肪如何导致癌症还不太清楚。我们在很大程度上忽视了对这种疾病有害或有益的饮食脂肪的相对数量和类型。我们的建议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抑制和omega-6刺激前列腺癌作用中的作用。

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. 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.