HIF-1alpha promotes survival of prostate cells at a high zinc environment.
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-1alpha was found to be robustly expressed in epithelial layers containing high zinc levels. Moreover, in cultured prostate cells, HIF-1alpha 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-1alpha in vivo and in vitro. The HIF-1alpha 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-1alpha was knocked-down by siRNA.


CONCLUSIONS
These results suggest that HIF-1alpha functions as an intrinsic defense molecule that enables prostate cells to survive in a zinc-rich environment.
Park
Sook-Eun
SE
Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, Korea.
Park
Jong-Wan
JW
Cho
Young-Suk
YS
Ryu
Ji-Hye
JH
Paick
Jae-Seung
JS
Chun
Yang-Sook
YS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D011467:Prostate / Q000187:drug effects / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D017967:Zinc Compounds / Q000633:toxicity*
D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D017967:Zinc Compounds; D011393:Procollagen-Proline Dioxygenase; D046988:Proteasome Endopeptidase Complex