HORMONAL REGULATION OF PROSTATE CITRATE PRODUCTION

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Prostate cancer is the second leading cause of cancer deaths in males, and combined with benign prostatic hyperplasia (BPH), represents the leading neoplastic disease in men. In humans, the prostate gland has the unique function of producing and secreting extraordinarily high levels of citrate. These physiology functions of the prostate are regulated by testosterone and prolactin. The lost of the capability to produce citric acid is a characteristic of prostate cancer and is among the first metabolic changes associated with the development of prostate malignancy. Glandular BPH on the other hand is characterized by excessive proliferation of citrate producing secretory epithelial cells and thus an even higher level of citrate that the normal gland. The two key enzymes directly involved in citrate synthesis by prostate epithelial cells are mitochondrial aspartate aminotransferase (mAAT) and pyruvate dehydrogenase (PDH). Both of these enzymes are regulated by testosterone and prolactin. The broad objectives of this grant application are to elucidate the mechanisms by which prolactin regulates expression and activity of these intermediary metabolic enzymes; to elucidate the intracellular signaling pathways involved and to use this information to develop new approaches to the diagnosis, prevention, and treatment of prostate neoplastic disease. The general hypotheses of this grant application are: The mAAT and E1a genes contain a TPA response element (TPA) that is responsible for prolactin regulation of expression via PKC; that the cell specificity of this regulation is achieved by prolactin activation of specific PKC isoforms (particularly PKC epsilon) which activate selective transcription factors (particularly AP-I); and that prolactin increases the active form of E1a which increases pyruvate oxidation. The specific aims proposed to test these hypotheses are (l) to establish that PKC epsilon and activator protein-I (AP-l) mediate prolactin regulation of mAAT and PDHE1 alpha expression; (2) to determine if prolactin increases pyruvate oxidation.