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.
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.
|Weylandt, Karsten H; Chen, Yong Q; Lim, Kyu et al. (2015) Ï‰ -3 PUFAs in the Prevention and Cure of Inflammatory, Degenerative, and Neoplastic Diseases 2014. Biomed Res Int 2015:695875|
|Chen, Haiqin; Hao, Guangfei; Wang, Lei et al. (2015) Identification of a critical determinant that enables efficient fatty acid synthesis in oleaginous fungi. Sci Rep 5:11247|
|Bernardo, M Margarida; Kaplun, Alexander; Dzinic, Sijana H et al. (2015) Maspin Expression in Prostate Tumor Cells Averts Stemness and Stratifies Drug Sensitivity. Cancer Res 75:3970-9|
|Hao, Guangfei; Chen, Haiqin; Gu, Zhennan et al. (2015) Metabolic engineering of Mortierella alpina for arachidonic acid production with glycerol as carbon source. Microb Cell Fact 14:205|
|Shi, Haisu; Chen, Haiqin; Gu, Zhennan et al. (2015) Molecular mechanism of substrate specificity for delta 6 desaturase from Mortierella alpina and Micromonas pusilla. J Lipid Res 56:2309-21|
|Gu, Zhennan; Shan, Kai; Chen, Haiqin et al. (2015) n-3 Polyunsaturated Fatty Acids and their Role in Cancer Chemoprevention. Curr Pharmacol Rep 1:283-294|
|Suburu, Janel; Shi, Lihong; Wu, Jiansheng et al. (2014) Fatty acid synthase is required for mammary gland development and milk production during lactation. Am J Physiol Endocrinol Metab 306:E1132-43|
|Yang, B; Chen, H; Gu, Z et al. (2014) Synthesis of conjugated linoleic acid by the linoleate isomerase complex in food-derived lactobacilli. J Appl Microbiol 117:430-9|
|Suburu, Janel; Lim, Kyu; Calviello, Gabriella et al. (2014) RE: Serum phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl Cancer Inst 106:dju023|
|Gu, Zhennan; Suburu, Janel; Chen, Haiqin et al. (2013) Mechanisms of omega-3 polyunsaturated fatty acids in prostate cancer prevention. Biomed Res Int 2013:824563|
Showing the most recent 10 out of 18 publications