The role of zinc in the molecular and cellular events in the prostate Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/0c483n028

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  • Zinc is an essential mineral that is integral to many proteins and transcription factors that regulate key cellular functions. The normal prostate accumulates high concentrations of zinc; however, malignant tissues have significantly lower zinc levels. This unique relationship between zinc and the prostate has sparked interest in the role of zinc in protecting against prostate cancer development. The purpose of this dissertation was to examine the molecular changes that occur in the prostate in response to alterations in cellular zinc. For our approach, we examined the effects of zinc deficiency and supplementation in normal and prostate cancer cells, respectively. Zinc supplementation decreased cell growth and viability in both prostate cancer (PC-3) and benign prostate hyperplasia (BPH-1) cells, however BPH-1 cells were more sensitive to zinc compared to PC-3 cells. Differential responses to zinc were also observed for Bcl-2:BAX expression and NFκB expression and activity. These findings suggest that zinc may differentially affect regulators of apoptosis in BPH-1 and PC-3 cells, and that zinc may control cellular proliferation in prostate cancer and hyperplasia. Secondly, we examined molecular changes in the normal prostate cells with zinc deficiency both in vitro and in vivo. Zinc deficiency increased single strand DNA breaks in normal prostate epithelial cells (PrEC). Importantly, zinc deficiency also up-regulated gene and nuclear protein expression of p53, but no change in p53 DNA binding activity or gene expression of the downstream p53 targets BAX and p21 was observed. These studies indicate that zinc deficiency increased DNA damage and impaired activity of critical zinc dependent transcription factors responsible for mediating the DNA damage response. In vivo, microarray analysis revealed that dietary zinc deficiency caused differential regulation of genes involved in prostate cancer and cell signaling. Interestingly, dietary zinc deficiency decreased prostate zinc in wild-type (WT) but not Cu/Zn SOD over-expressing (SOD⁺⁺⁺) animals, suggesting that over-expression of Cu/Zn SOD may protect against zinc loss. Differential expression of zinc transporters may explain this effect, as expression of zip1 and zip3 were significantly lower in SOD⁺⁺⁺ animals. Together these studies suggest that zinc may play a critical role in the maintenance of a healthy prostate.
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