It is well established that prostate cancer (PCa), as contrasted with normal prostate or benign prostatic hyperplasia (BPH), is consistently characterized by dramatic decreases in citrate and zinc levels. Strong and compelling evidence exists that implicate a significant role of altered zinc accumulation in the regulation of citrate metabolism of prostate epithelial cells associated with the development and progression of prostate malignancy. Our broad objectives are to establish the mechanism and regulation of zinc accumulation in normal prostate cells; to determine the alterations that accounts for the loss of zinc accumulation associated with the pathogenesis and progression of malignancy; to establish mechanisms to restore zinc accumulation in malignant and pre-malignant prostate cells; to use this information in the development of new approaches to the diagnosis, treatment and perhaps prevention of prostate malignancy. Normal prostate glandular epithelial cells have the major function and capability of accumulating and secreting the highest levels of both citrate and zinc in the body. We recently established the important link between zinc and citrate; i.e., zinc inhibits (mitochondrial) m-aconitase activity and citrate oxidation of citrate-producing prostate epithelial cells. In PCa, prostate cells undergo a transformation from zinc-accumulating, citrate-producing sane cells to citrate oxidizing malignant cells, due to the lost ability to accumulate high zinc levels. This metabolic transformation occurs early in malignancy and is an apparent requirement for progression of the malignancy. Thus, the mechanism involved in the lost ability to accumulate zinc, which permits the alteration in citrate metabolism, is a key relationship in prostate malignancy.
The specific aims of the proposal are: 1. To establish the mechanism by which ZIP1 facilitates the transport of zinc from plasma into the cell. 2. To determine the structure of the regulatory region of the ZIP1 gene that confers prolactin and testosterone regulation. 3. To establish that altered expression of ZIP1 alters the tumorigenicity of prostate cells (PC-3 and LNCaP). 4. To determine if decreases expression of ZIP1 and decreased zinc accumulation are characteristics of malignant cells in prostate cancer.
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