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.

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

“…As expected, BIC-occupied AR remained unaffected by the T877A mutation, and showed no change in response to N-CoR. This is in accordance with the previous finding that the BIC-induced AR conformation is not changed by the T877A mutation [9], and with the ability of T877A-AR from LNCaP cells to recruit N-CoR to the PSA promoter [25] and subsequently inhibit PSA production in the presence of BIC [43].…”

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

“…The compound induced no N/C interaction of AR in the absence of DHT (Fig. 2B) as OHF and BIC (52,53). These results suggest that DIMN inhibits the dimerization of the AR.…”

Cross-talk between the Androgen Receptor and the Liver X Receptor

“…2). Although the casodex mode of action remains controversial, one group has shown that casodex allows translocation of AR into the nucleus and DNA binding in LNCaP cells (43) but prevents NH 2 /COOHterminal interaction and coactivator recruitment (43,44). This casodex antagonism occurred independently of the corepres- sors NCoR and SMRT (44), suggesting competition for coactivators rather than corepressors.…”