title: Hypoxia-independent downregulation of hypoxia-inducible factor 1 targets by androgen deprivation therapy in prostate cancer.
abstract: OBJECTIVE
  We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred.
  
  
  METHODS
  Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry.
  
  
  RESULTS
  A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001).
  
  
  CONCLUSIONS
  AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to tumor regression. HIF1α expression is probably not a useful hypoxia biomarker during ADT in prostate cancer.
authors.affiliation: Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Harald Bull
authors.initials: HB
authors.lastname: Ragnum
authors.forename: Kathrine
authors.initials: K
authors.lastname: Røe
authors.forename: Ruth
authors.initials: R
authors.lastname: Holm
authors.forename: Ljiljana
authors.initials: L
authors.lastname: Vlatkovic
authors.forename: Jahn Marthin
authors.initials: JM
authors.lastname: Nesland
authors.forename: Eva-Katrine
authors.initials: EK
authors.lastname: Aarnes
authors.forename: Anne Hansen
authors.initials: AH
authors.lastname: Ree
authors.forename: Kjersti
authors.initials: K
authors.lastname: Flatmark
authors.forename: Therese
authors.initials: T
authors.lastname: Seierstad
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lilleby
authors.forename: Heidi
authors.initials: H
authors.lastname: Lyng
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy / Q000379:methods; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods* / Q000706:statistics & numerical data; D017273:Goserelin / Q000627:therapeutic use; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D060828:Induction Chemotherapy / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009570:Nitriles / Q000627:therapeutic use; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D011897:Random Allocation; D011944:Receptors, Androgen / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology; D014105:Tosyl Compounds / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D051793:Hypoxia-Inducible Factor 1; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D017273:Goserelin; C053541:bicalutamide; D017430:Prostate-Specific Antigen