PROLACTIN REGULATION OF PROSTATE CITRATE PRODUCTION

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Prostate cancer is now the second leading cause of cancer deaths in males, and combined with benign prostatic hyperplasia, now represents the leading neoplastic disease in man. In humans, the prostate gland has the unique function of producing and secreting extraordinarily high levels of citric acid. The major distinguishing characteristic of prostate cancer is the transformation of citrate producing prostate epithelial cells to malignant cells which are incapable of producing citrate. Our broad objectives are to elucidate and to understand the unique metabolic relationships which characterize the ability of prostate cells to achieve this function; to understand the mechanisms by which prolactin and other hormones regulate this major function; to elucidate the metabolic and hormonal alterations associated with prostate neoplasms; and to use this information for new approaches in the diagnosis, prevention, and treatment of prostate neoplasms. It has now been established that prolactin is an important regulator of prostate citrate production. The specific aims of this program is to elucidate the mechanisms by which prolactin regulates citrate synthesis of normal prostate epithelial cells. The major relationship to be addressed is the mechanism by which prolactin regulates mitochondrial aspartate aminotransferase (mAAT) and pyruvate dehydrogenase (PDH) E1alpha, the two key enzymes involved in prostate citrate synthesis. The focus of the proposed studies will be on prolactin regulation of expression of the mAAT and E1alpha genes and the role of protein kinase C (PKC). Once these relationships are established with normal prostate cells involving rat lateral prostate, the role of "prolactin-PKC-gene regulation" in human malignant prostate cells (LNCaP, PC-4 Du-145) will be established. This will represent the first concerted characterization of citrate-related metabolism in human prostate epithelial cells.