title: The role of hypoxia-inducible factor-1α and -2α in androgen insensitive prostate cancer cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The induction patterns of HIF-1α and -2α after treatment with ZnSO4 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 ZnSO4-treated DU145 cells using Western blotting.
  
  
  RESULTS
  ZnSO4 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 ZnSO4 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.
authors.affiliation: Department of Urology, Seoul National University, Bundang Hospital, Seongnam, Korea.
authors.forename: Chang Wook
authors.initials: CW
authors.lastname: Jeong
authors.forename: Cheol Yong
authors.initials: CY
authors.lastname: Yoon
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Sung Kyu
authors.initials: SK
authors.lastname: Hong
authors.forename: Seok-Soo
authors.initials: SS
authors.lastname: Byun
authors.forename: Cheol
authors.initials: C
authors.lastname: Kwak
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D000077210:Sunitinib; D043823:Taxoids / Q000494:pharmacology; D019287:Zinc Sulfate / Q000494:pharmacology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000077143:Docetaxel; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D007334:Insulin-Like Growth Factor I; D009536:Niacinamide; D010671:Phenylurea Compounds; D019859:Proto-Oncogene Proteins c-met; D011758:Pyrroles; D000077157:Sorafenib; D000077210:Sunitinib; D043823:Taxoids; D019287:Zinc Sulfate; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human