Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Prostate cancer (PCa) relapse after androgen deprivation therapy (ADT) is linked to high androgen receptor (AR) activity.
• Mechanisms of AR activation in ADT-resistant PCa are not fully understood.
• Bicalutamide, a common AR antagonist, typically inhibits AR but its role in resistant tumors requires clarification.

Purpose of the Study:

• To investigate the mechanism of AR activation by bicalutamide in androgen-independent PCa.
• To determine if bicalutamide can stimulate AR nuclear translocation and DNA binding in resistant PCa.
• To explore the role of coactivator recruitment in bicalutamide-mediated AR signaling.

Main Methods:

• Studied nuclear AR expression in bicalutamide-treated PCa cells.
• Utilized a VP16-AR fusion protein to assess AR DNA binding in vivo.
• Performed chromatin immunoprecipitation (ChIP) to confirm AR binding to the prostate-specific antigen enhancer.
• Assessed AR N- and C-terminal interactions and steroid receptor coactivator (SRC) recruitment.

Main Results:

• Bicalutamide induced nuclear AR expression and translocation in androgen-independent PCa cells.
• Bicalutamide-liganded AR demonstrated specific DNA binding in vivo and in LNCaP cells.
• Bicalutamide did not promote AR N/C-terminal interaction or SRC recruitment.
• SRC transfection partially restored AR activity in the presence of bicalutamide.

Conclusions:

• Bicalutamide can stimulate the binding of a transcriptionally inactive AR to DNA in PCa.
• Altered expression of coactivators or corepressors may be a key mechanism driving bicalutamide resistance in PCa.
• Findings provide insight into therapeutic resistance in advanced prostate cancer.