For more than 2 decades, epidemiologic studies have been reported on the effect of dietary fat on the risk of prostate cancer. Experimental data indicate that n-3 polyunsaturated fatty acids (PUFAs) inhibit whereas n-6 PUFAs stimulate prostate cancer cell growth. However; the mechanism of PUFA's effect is unknown. Fish oil is a rich source of n-3 polyunsaturated fatty acids. We hypothesize that n-3 PUFAs incorporate into the sn-2 position of phospholipids, and the n-3 PUIA-enriched phospholipids regulate expression of genes resulting in prostate cell growth inhibition. In this project, we will pursue two parallel approaches to investigate the molecular mechanism involved in the growth inhibition of prostate cells by n-3 PUFA. First, we will use a candidate pathway approach, focusing on the phosphoinositide signaling pathway which is affected by fish oil diet, and which plays a central role in regulating prostate cell growth and survival. Secondly, we will perform a general unbiased screening to identify candidate genes and phospholipids regulated by fish oil diet.
Our specific aims are: Assess the effect of n-3 and n-6 PUFA on tumor incidence. Pten+"""""""";Nkx3.1 """""""" mice will be fed with n-3 PUFA (fish oil)-enriched, n-6 PUFA-enriched and control diet for a period of 6 months. Prostate cancer incidence will be determined in the dorsolateral''prostate; Determine the effect of fish oil diet on the phoshoinositide signaling pathway. Cancer lesions develop in the dorsolateral but not in the ventral gland of Pten+"""""""";Nkx3.1-1"""""""" mice. The dorsolateral and ventral prostates will be obtained from diet groups. The levels of phosphoinositides will be measured and the structure of phosphoinositides will be determined. Cell proliferation and apoptosis indexes will be analyzed. mRNA and protein levels of P13K, Pten, AKT, PDK and DIP13 as well as AKT and PDK activity will be compared. Normal and tumor prostate cells will be treated with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their effect on prostate cell growth and apoptosis will be investigated; Characterize DhosDholiDid and gene expression profiles regulated by diet. The dorsolateral and ventral glands will be laser capture microdissected. Phospholipid (PC, PS, PE, and PI) and mRNA expression profiles will be determined by mass spectrometry and DNA microarray, respectively. Phospholipids and genes that are affected by diet will be identified. The novelty of our application is to use a genetically-defined, immune-competent, orthotopic mouse prostate cancer model and composition-defined diet, in conjunction with cell culture system, to study the effect and mechanism of dietary fat on the phosphoinositide signaling pathway in prostate. Furthermore, we take advantage of our strengths in genomics and lipidomics.' For the first time, molecular changes (mRNA and lipid) associated with fish oil diet in the prostate will be comprehensively and systematically analyzed.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZCA1-SRRB-D (J2))
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Kim, Young Shin
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Wake Forest University Health Sciences
Schools of Medicine
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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
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
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
Hao, Guangfei; Chen, Haiqin; Du, Kai et al. (2014) Increased fatty acid unsaturation and production of arachidonic acid by homologous over-expression of the mitochondrial malic enzyme in Mortierella alpina. Biotechnol Lett 36:1827-34
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
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
Wang, Mingxuan; Chen, Haiqin; Gu, Zhennan et al. (2013) ?3 fatty acid desaturases from microorganisms: structure, function, evolution, and biotechnological use. Appl Microbiol Biotechnol 97:10255-62
Suburu, Janel; Gu, Zhennan; Chen, Haiqin et al. (2013) Fatty acid metabolism: Implications for diet, genetic variation, and disease. Food Biosci 4:1-12
Chen, Haiqin; Gu, Zhennan; Zhang, Hao et al. (2013) Expression and purification of integral membrane fatty acid desaturases. PLoS One 8:e58139

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