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.
Highlights
The majority of prostate cancers (PCa)1 are androgen-dependent and respond to androgen deprivation therapies, which include orchiectomy or administration of leutinizing hormonereleasing hormone agonists to suppress testicular androgen production [1]
To determine whether nuclear localization was inhibited by bicalutamide in normal prostate epithelium, mice were treated with bicalutamide (1 mg in 0.1 ml of PBS by intraperitoneal injection every other day for 2 weeks), and their prostates were examined
Immunohistochemistry showed strong nuclear androgen receptor (AR) expression in the prostate epithelium of both untreated and bicalutamide-treated mice (Fig. 1, E and F). These results demonstrated that bicalutamide did not prevent AR nuclear translocation in normal or malignant prostate epithelial cells
Summary
The most widely used AR antagonists have been the steroidal drug cyproterone acetate and the nonsteroidal drugs flutamide and bicalutamide, which are all competitive antagonists of androgen binding [16]. Cyproterone acetate has significant AR agonist activity, whereas weak agonist activity has been shown for hydroxyflutamide, the active metabolite of flutamide [17, 18]. Previous studies have shown bicalutamide to be a pure antagonist of wild type and identified mutant ARs [18, 19]. The unliganded AR associates with a heat shock protein 90 (HSP90) chaperone complex that facilitates ligand binding with subsequent conformational changes resulting in AR homodimerization, nuclear translocation, DNA binding, and transcriptional activation [20]. Previous studies in cell lines have indicated that the bicalutamide-liganded AR remains cytoplasmic- and HSP90-associated, which is not consistent with transcriptional activity [21].
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