The Role of Hypoxia-Inducible Factor-1α and-2α in Androgen Insensitive Prostate Cancer Cells

Objectives: The aim of this study was to investigate the effects of induction and knocking down of hypoxia-inducible factor (HIF)-1 alpha and/or -2 alpha on tumor biology in androgen insensitive prostate cancer cell lines. Materials and methods: The induction patterns of HIF-1 alpha and -2 alpha after treatment with ZnSO4 were evaluated in PC3 and DU145 cells. Both cell lines were transfected with siRNA targeted against HIF-1 alpha and/or -2 alpha, and the expression patterns of these 2 HIF isoforms were examined. We next performed cell counting Kit-8 (CCK-8) assays and matrigel invasion assays. Potential additive effects of HIP blockade to chemotherapy (docetaxel) or target agents (sunitinib and sorafenib) were examined. In addition, gene expression changes were determined in ZnSO4-treated DU145 cells using Western blotting. Results: ZnSO4 affected the expression of HIP in a dose-dependent manner. HIP expression was increased within the first 3 hours but then decreased. Cells in which HIF-1 alpha and/or -2 alpha had been knocked down using siRNA showed decreased cell viability. Invasion abilities were increased by ZnSO4 treatment in both cell lines overexpressing HER However, invasion potencies were decreased in response to treatment with HIP siRNAs. Blocking HIF prominently augmented the antitumor effects of target agents. The underlying mechanism could be associated with p21, cMET, IGF-1, and GLUT-1. Conclusions: Our results demonstrate that HIF-1 alpha and -2 alpha are important for cell proliferation and invasion ability in prostate cancer. Together, our results indicate that combinations of target agents with HIP knockdown may represent a promising strategy for the treatment of prostate cancer. (C) 2013 Elsevier Inc. All rights reserved.