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


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.
Saporita
Anthony J
AJ
Department of Urology, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Ai
Junkui
J
Wang
Zhou
Z
D016227:Benzoquinones / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
C410798:AR protein, human; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008024:Ligands; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; C112765:tanespimycin; D017430:Prostate-Specific Antigen