Survivin mediates prostate cell protection by HIF-1alpha against zinc toxicity.
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-1alpha is expressed concomitantly with the accumulation of zinc in the epithelial cells of normal rat prostates, the zinc ion stabilizes HIF-1alpha in prostate cells, and that HIF-1alpha protects prostate cells from zinc toxicity. In the present study, the authors addressed the mechanism responsible for the protective effect of HIF-1alpha 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-1alpha 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.


CONCLUSIONS
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-1alpha-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.
Yun
Young-Joo
YJ
Department of Biomedical Sciences, Seoul National University College of Medicine, Chongno-gu, Seoul, Korea.
Li
Shan-Hua
SH
Cho
Young-Suk
YS
Park
Jong-Wan
JW
Chun
Yang-Sook
YS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002712:Chlorides / Q000008:administration & dosage; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D011467:Prostate / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D015032:Zinc / Q000378:metabolism / Q000633:toxicity*; D017967:Zinc Compounds / Q000008:administration & dosage
C516989:Birc5 protein, rat; D002712:Chlorides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D017967:Zinc Compounds; D012313:RNA; C016837:zinc chloride; D015032:Zinc