Prostate cancer (PCa) is the second leading cause of cancer deaths in males. The diagnosis, treatment, and prevention of PCa are important contemporary issues. New approaches are required to address this major health problem. Important fundamental information and understanding of the pathogenesis and progression are seriously lacking; which contributes to the slow progress in addressing these issues. Compelling evidence now implicates the involvement of altered zinc accumulation and citrate-related metabolism in the pathogenesis and progression of PCa. The most consistent hallmark characteristic of PCa is the inability of the malignant cells to accumulate zinc and citrate as contrasted with the extremely high accumulation of zinc and citrate associated with normal prostate and benign prostatic hyperplasia (BPH). The consistency of this metabolic change is revealed by the fact that in situ MRS determination of prostate citrate levels now provides the most accurate and sensitive test for the detection and localization of malignancy. The key reaction in the metabolic transformation of non-malignant citrate-producing prostate epithelial cells to citrate-oxidizing malignant cells is mitochondrial (m-) aconitase. The expression and level of m-aconitase are regulated by hormones (testosterone and prolactin) and by zinc specifically in prostate cells. In this application, the mechanism and specificity of hormonal regulation of the m-aconitase gene in normal and malignant prostate cells will be established. The role of zinc in modulating the activity and equilibrium of m-aconitase will be investigated. The studies will be performed with normal fresh prostate epithelial cells obtained from rat prostate tissue; and with human malignant prostate cell lines. The long-term objectives are to understand the unique metabolic relationships associated with the alteration of citrate-related metabolism of normal and malignant prostate cells; to establish the role of zinc and hormones in this altered metabolism, and the implications in the pathogenesis and progression of malignancy. This information will provide new approaches to the diagnosis, prevention, and treatment of PCa.
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