HIF-1α promotes survival of prostate cells at a high zinc environment
HIF-1α promotes survival of prostate cells at a high zinc environment
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DOI：
10.1002/pros.20641
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发表时间：
2007-10-01
期刊：
影响因子：
2.8
通讯作者：
Chun, Yang-Sook
中科院分区：
文献类型：
--
作者：
Park, Sook-Eun;Park, Jong-Wan;Chun, Yang-Sook
背景前列腺含有极高浓度的锌，这可能是男性生殖所需的。虽然锌对许多细胞功能是必需的，但过量的锌通常会诱导细胞毒性。然而，尽管暴露于高锌环境，前列腺细胞存活并增殖。因此，本研究的目的是确定赋予前列腺细胞克服锌毒性的能力的内在分子种类。免疫组织化学、组织荧光锌染色、蛋白质印迹、体外结合试验、免疫沉淀、半胱天冬酶活性试验和蛋白酶体活性试验。在大鼠和人类前列腺中，发现HIF-1 α在含有高锌水平的上皮层中强烈表达。此外，在培养的前列腺细胞中，即使在常氧条件下，HIF-1 α的表达也是锌依赖性诱导的。从机制上讲，锌离子抑制HIF-1-脯氨酰羟化酶（PHD）的活性，因此在体内和体外阻断了von Hippel-Lindau肿瘤抑制蛋白（pVHL）与HIF-1 α的结合。HIF-1 α的稳定化是由锌离子诱导的氧化应激介导的。即使用高浓度的锌离子处理前列腺细胞很长时间，也只有10%的细胞表现出凋亡性死亡。然而，在用siRNA敲低HIF-1 α a后，凋亡细胞的数量增加了3倍。这些结果表明，HIF-1 α作为一种内在的防御分子，使前列腺细胞能够在富含锌的环境中生存。
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-1 alpha was found to be robustly expressed in epithelial layers containing high zinc levels. Moreover, in cultured prostate cells, HIF-1 alpha 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-1 alpha in vivo and in vitro. The HIF-1 alpha 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-1 alpha a was knocked-down by siRNA.CONCLUSION. These results suggest that HIF-1 alpha functions as an intrinsic defense molecule that enables prostate cells to survive in a zinc-rich environment.