Zinc ion dyshomeostasis increases resistance of prostate cancer cells to oxidative stress via upregulation of HIF1α.

Zinc ions (Zn) are known to influence cell survival and proliferation. However the homeostatic regulation of Zn and their role in prostate cancer (PC) progression is poorly understood. Therefore the subcellular distribution and uptake of Zn in PC cells were investigated. Inductively coupled plasma mass spectroscopy and fluorescent microscopy with the Zn-specific fluorescent probe FluoZin-3 were used to quantify total and Zn, respectively, in the normal prostate epithelial cell line (PNT1A) and three human PC cell lines (PC3, DU145 and LNCaP). The effects of Zn treatment on proliferation and survival were measured using MTT assays and using mouse xenografts. The ability of Zn to protect against oxidative stress via a HIF1α-dependent mechanism was investigated using a HIF1α knock-down PC3 model. Our results demonstrate that the total Zn concentration in normal PNT1A and PC cells is similar, but PC3 cells contain significantly higher free Zn than PNT1A cells ( < 0.01). PNT1A cells can survive better in the presence of high concentrations of Zn than PC3 cells. Exposure to 10 µM Zn over 72 hours significantly reduces PC3 cell proliferation but not . Zn increases PC3 cell survival up to 2.3-fold under oxidative stress, and this protective effect is not seen in PNT1A cells or in a HIF1α-KD PC3 cell model. A state of Zn dyshomeostasis exists in PC. HIF1α is an integral component of a Zn-dependent protective mechanism present in PC3 cells. This pathway may be clinically significant through its contribution to castrate-resistant PC survival.