OBJECTIVES: The aim of this study was to investigate the effects of induction and knocking down of hypoxia-inducible factor (HIF)-1α and/or -2α on tumor biology in androgen insensitive prostate cancer cell lines.
MATERIALS AND METHODS: The induction patterns of HIF-1α and -2α after treatment with ZnSO(4) were evaluated in PC3 and DU145 cells. Both cell lines were transfected with siRNA targeted against HIF-1α and/or -2α, 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 HIF blockade to chemotherapy (docetaxel) or target agents (sunitinib and sorafenib) were examined. In addition, gene expression changes were determined in ZnSO(4)-treated DU145 cells using Western blotting.
RESULTS: ZnSO(4) affected the expression of HIF in a dose-dependent manner. HIF expression was increased within the first 3 hours but then decreased. Cells in which HIF-1α and/or -2α had been knocked down using siRNA showed decreased cell viability. Invasion abilities were increased by ZnSO(4) treatment in both cell lines overexpressing HIF. However, invasion potencies were decreased in response to treatment with HIF 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-1α and -2α are important for cell proliferation and invasion ability in prostate cancer. Together, our results indicate that combinations of target agents with HIF knockdown may represent a promising strategy for the treatment of prostate cancer.
Written by:
Jeong CW, Yoon CY, Jeong SJ, Hong SK, Byun SS, Kwak C, Lee SE Are you the author?
Department of Urology, Seoul National University, Bundang Hospital, Seongnam, Korea
Reference: Urol Oncol. 2012 Apr 24
doi: 10.1016/j.urolonc.2012.03.022
PubMed Abstract
PMID: 22537539