The Role of Central Metabolism in Prostate Cancer Progression

PUBLIC ABSTRACT

It is estimated that 222,389 men in the United States will be diagnosed with prostate cancer (PCa) in 2007 and 27,050 will die of the disease. Treatment options are limited; the most common therapy for local prostate cancer, surgery, can cause incontinence or impotence while no curative therapy exists for advanced, metastatic disease. As it is a particularly slow growing disease, prostate cancer does not typically respond well to chemotherapy, which primarily targets rapidly dividing cells. The slow growth rate of prostate cancer, coupled with the advanced age at which this disease generally strikes, typically provides an opportunity for meaningful intervention. Any treatment that slows the progression of prostate cancer would likely make the disease clinically irrelevant so that men would die with prostate cancer rather than from it. This translational research project is based on the epidemiological and preliminary studies demonstrating that omega-3 fatty acids, found in fish oil, may prevent prostate cancer disease progression. Epidemiological studies suggest that intake of omega-3 polyunsaturated fatty acids (PUFAs) decrease prostate cancer risk while intake of omega-6 PUFAs, found in plant oils, increases risk. We as well as others have demonstrated that the metabolites of omega-6 and omega-3 PUFAs directly impact PCa tumor development and the ability to do so depends on both diet and the levels of enzymes responsible for metabolizing these PUFAs: Omega-3 metabolites activate anti-tumorigenic pathways and omega-6 metabolites active pro-tumorigenic ones. Moreover, we found that omega-3 PUFAs inhibit the activity of an enzyme central to the synthesis of monounsaturated fatty acids. This fatty acid synthesis leads to increased levels of many proteins, including those involved in PUFA metabolism as well as in other pathways that may affect cancer.

Based on the results of our preliminary studies, we hypothesize that omega-3 fatty acid will be highly effective in suppressing growth of human prostate cancer due to its ability to (a) suppress fatty acid synthesis in the prostate tumor cells, and (b) inhibit pro-tumorigenic metabolite formation in favor of anti-tumorigenic pathway molecules. We propose to treat patients that are diagnosed with prostate cancer with fish-oil containing omega-3 fatty acids or control lipid (oleic acid) for 5 weeks prior to prostatectomy and then use the tissue removed during surgery to precisely identify how omega-3 fatty acids alter the pro- and anti-tumorigenic pathways concomitantly with the phosphoproteins. This project requires the expertise of each investigator involved: Dr. Kelavkar's expertise focuses on the administration of fatty acids and PUFA metabolism; Dr. Pflug has extensive experience in fatty acid synthesis; and Dr. Conrads is an expert in identifying proteins and modifications of proteins such as phosphoproteins associated with a disease state. Successful completion of this study will help (1) establish omega-3 PUFA as a preventative agent for prostate cancer progression, (2) determine how omega-3 impacts prostate cancer, and (3) identify markers that can be used to assess omega-3 actions. By addressing these issues, our goal is to lay the groundwork for larger clinical studies. The potential of omega-3 fatty acids as a non-toxic dietary agent that can delay onset and/or progression of prostate cancer could, in the long-term, have a profound impact on the overall incidence of prostate cancer especially in the "baby boomer" population. Omega-3 may also have an especially profound impact on those men who cannot undergo surgery due to advanced age or overall poor health. Importantly, a dietary intervention approach using omega-3 fatty acids could be rapidly implemented into the patient population with minimal risk.