title: Galeterone prevents androgen receptor binding to chromatin and enhances degradation of mutant androgen receptor.
abstract: OBJECTIVE
  Galeterone inhibits the enzyme CYP17A1 and is currently in phase II clinical trials for castration-resistant prostate cancer (CRPC). Galeterone is also a direct androgen receptor (AR) antagonist and may enhance AR degradation. This study was undertaken to determine the molecular basis for AR effects and their therapeutic potential.
  
  
  METHODS
  Effects of galeterone on AR expression and activities were examined in prostate cancer cell lines.
  
  
  RESULTS
  Similar to the AR antagonist enzalutamide, but in contrast to bicalutamide, galeterone did not induce binding of a constitutively active VP16-AR fusion protein to reporter genes and did not induce AR recruitment to endogenous androgen-regulated genes based on chromatin immunoprecipitation. Galeterone at low micromolar concentrations that did not induce cellular stress responses enhanced AR protein degradation in LNCaP and C4-2 cells, which express a T878A mutant AR, but not in prostate cancer cells expressing wild-type AR. Further transfection studies using stable LNCaP and PC3 cell lines ectopically expressing wild-type or T878A-mutant ARs confirmed that galeterone selectively enhances degradation of the T878A-mutant AR.
  
  
  CONCLUSIONS
  Similar to enzalutamide, galeterone may be effective as a direct AR antagonist in CRPC. It may be particularly effective against prostate cancer cells with the T878A AR mutation but may also enhance degradation of wild-type AR in vivo through a combination of direct and indirect mechanisms. Finally, these findings show that conformational changes in AR can markedly enhance its degradation and thereby support efforts to develop further antagonists that enhance AR degradation.
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Ziyang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cai
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Shuai
authors.initials: S
authors.lastname: Gao
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Simon
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Shen
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts sbalk@bidmc.harvard.edu.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D006801:Humans; D008297:Male; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000730:Androstadienes; D001562:Benzimidazoles; D002843:Chromatin; D050505:Mutant Proteins; D011944:Receptors, Androgen; C500627:3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene