Premium
Survivin mediates prostate cell protection by HIF‐1α against zinc toxicity
Author(s) -
Yun YoungJoo,
Li ShanHua,
Cho YoungSuk,
Park JongWan,
Chun YangSook
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21152
Subject(s) - toxicity , prostate , prostate cancer , survivin , medicine , cancer research , biology , cancer
BACKGROUND The prostate contains extremely high concentrations of zinc, but survives and grows without apparent injury. This begs the question as to how prostate cells avoid the toxic effects of zinc. In a previous study, the authors found that; HIF‐1α is expressed concomitantly with the accumulation of zinc in the epithelial cells of normal rat prostates, the zinc ion stabilizes HIF‐1α in prostate cells, and that HIF‐1α protects prostate cells from zinc toxicity. In the present study, the authors addressed the mechanism responsible for the protective effect of HIF‐1α in a high zinc environment. METHODS Immunofluorescent staining, immunoblotting, reverse transcription‐polymerase chain reaction, reporter assay, and cell cycle analysis. RESULTS Survivin was induced by ZnCl 2 in a HIF‐1 dependent manner in both DU‐145 and PNT2 prostate cells. Furthermore, HIF‐1 induced survivin expression at the transcriptional level and the induction of survivin was abolished by HIF‐1α knock‐down. In addition, HIF‐1‐dependent survivin overexpression promoted prostrate cell survival and prevented cell arrest in the presence of high zinc concentrations, and si‐survivin transfected cells under zinc rich conditions contained markedly higher levels of cleaved caspase‐9 and PARP than si‐con transfected cells. Finally, survivin expression patterns well matched rat prostate proliferation statuses. CONCLUSION Under zinc rich conditions, prostate epithelial cells HIF‐1‐dependently express survivin, which promotes prostate cell proliferation, and prevents apoptosis and cell cycle arrest. Accordingly, the HIF‐1α‐survivin pathway appears to facilitate prostate cell survival and growth in zinc rich environments, and this pathway could be a therapeutic target for the treatment of prostate hyperplasia. Prostate 70: 1179–1188, 2010. © 2010 Wiley‐Liss, Inc.