The Hsp90 inhibitor, 17-AAG, prevents the ligand-independent nuclear localization of androgen receptor in refractory prostate cancer cells

• Published in: The Prostate 2007-04, Vol.67 (5), p.509-520
• Main Authors: Saporita, Anthony J., Ai, Junkui, Wang, Zhou
• Format: Article
• Language: English
• Subjects: androgen receptor; androgen-independence; Benzoquinones - pharmacology; Blotting, Northern; Blotting, Western; Cell Line, Tumor; Cell Nucleus - metabolism; Hsp90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; intracellular localization; Lactams, Macrocyclic - pharmacology; Ligands; Male; Neoplasms, Hormone-Dependent - genetics; Neoplasms, Hormone-Dependent - metabolism; prostate cancer; Prostate-Specific Antigen - antagonists & inhibitors; Prostate-Specific Antigen - biosynthesis; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Transcription, Genetic; Transfection
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.20541

BACKGROUND Androgen receptor (AR) is the key molecule in androgen‐refractory prostate cancer. Despite androgen ablative conditions, AR remains active and is necessary for the growth of androgen‐refractory prostate cancer cells. Nuclear localization of AR is a prerequisite for its transcriptional activation. We examined AR localization in androgen‐dependent and androgen‐refractory prostate cancer cells. METHODS AND RESULTS We demonstrate increased nuclear localization of a GFP‐tagged AR in the absence of hormone in androgen‐refractory C4‐2 cells compared to parental androgen‐sensitive human prostate cancer LNCaP cells. Analysis of AR mutants impaired in ligand‐binding indicates that the nuclear localization of AR in C4‐2 cells is truly androgen‐independent. The hsp90 inhibitor, 17‐allylamino‐17‐demethoxygeldanamycin (17‐AAG), inhibits basal PSA expression and disrupts the ligand‐independent nuclear localization of AR at doses much lower than required to inhibit androgen‐induced nuclear import. CONCLUSIONS Hsp90 is a key regulator of ligand‐independent nuclear localization and activation of AR in androgen‐refractory prostate cancer cells. Prostate 67: 509–520, 2007. © 2007 Wiley‐Liss, Inc.