HIF‐1α promotes survival of prostate cells at a high zinc environment

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Abstract
BACKGROUND The prostate contains extremely high concentrations of zinc, which may be required for male reproduction. Although zinc is essential for many cellular functions, excessive zinc induces cellular toxicity in general. However, despite exposure to high zinc environment, prostate cells survive and proliferate. Thus, the aim of this study was to identify the intrinsic molecular species that endow prostate cells with the ability to overcome zinc toxicity. METHODS Immunohistochemistry, histofluorescent zinc staining, Western blot, in vitro binding assay, immunoprecipitation, caspase activity assay, and proteasome activity assay. RESULTS In rat and human prostates, HIF-1α was found to be robustly expressed in epithelial layers containing high zinc levels. Moreover, in cultured prostate cells, HIF-1α expression was zinc-dependently induced even under normoxic conditions. Mechanistically, zinc ions inhibited HIF-1-prolyl hydroxylase (PHD) activity, and therefore blocked von Hippel-Lindau tumor suppressor protein (pVHL) binding to HIF-1α in vivo and in vitro. The HIF-1α stabilization was mediated by oxidative stress induced by zinc ion. Even when prostate cells were treated with high concentrations of zinc ion for extended times, only 10% of cells showed apoptotic death. However, this population of apoptotic cells was increased threefold after HIF-1α was knocked-down by siRNA. CONCLUSION These results suggest that HIF-1α functions as an intrinsic defense molecule that enables prostate cells to survive in a zinc-rich environment. Prostate 67: 1514–1523, 2007.

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