title: Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor.
abstract: Prostate cancers (PCa) that relapse after androgen deprivation therapy invariably express high levels of androgen receptor (AR) and AR-regulated genes. Most do not respond to secondary hormonal therapies, including AR antagonists, and the mechanisms of AR activation in these clinically androgen-independent tumors are unclear. Bicalutamide, the most widely used AR antagonist, is a competitive antagonist shown previously to stabilize AR association with cytosolic heat shock protein complexes. This study found nuclear AR expression in bicalutamide-treated androgen-independent PCa and found that bicalutamide could stimulate AR nuclear translocation. Moreover, specific DNA binding by the bicalutamide-liganded AR was demonstrated in vivo using a VP16-AR fusion protein and was confirmed by chromatin immunoprecipitation showing binding to the prostate-specific antigen enhancer in LNCaP PCa cells. Nonetheless, bicalutamide could not stimulate interactions between the AR N and C termini or recruitment of steroid receptor coactivator proteins (SRC-1 or -2), although SRC transfection augmented AR activity in the presence of dihydrotestosterone and inhibitory concentrations of bicalutamide. These results demonstrate that bicalutamide stimulates the assembly of a transcriptionally inactive AR on DNA and support altered coactivator (or corepressor) expression as a mechanism of bicalutamide-resistant androgen-independent PCa.
authors.affiliation: Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: David
authors.initials: D
authors.lastname: Masiello
authors.forename: Shinta
authors.initials: S
authors.lastname: Cheng
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Bubley
authors.forename: Michael L
authors.initials: ML
authors.lastname: Lu
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001517:Coleoptera; D005047:Etoposide / Q000378:metabolism; D051548:Histone Acetyltransferases; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D011944:Receptors, Androgen / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014105:Tosyl Compounds; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D009570:Nitriles; D051958:Nuclear Receptor Coactivator 2; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D014105:Tosyl Compounds; D014157:Transcription Factors; D005047:Etoposide; C053541:bicalutamide; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D017430:Prostate-Specific Antigen