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

Prostate. 2007 Apr 1;67(5):509-20. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Benzoquinones / pharmacology*
  • Blotting, Northern
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Lactams, Macrocyclic / pharmacology*
  • Ligands
  • Male
  • Neoplasms, Hormone-Dependent / genetics
  • Neoplasms, Hormone-Dependent / metabolism
  • Prostate-Specific Antigen / antagonists & inhibitors
  • Prostate-Specific Antigen / biosynthesis
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Transcription, Genetic
  • Transfection


  • AR protein, human
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Ligands
  • RNA, Neoplasm
  • Receptors, Androgen
  • tanespimycin
  • Prostate-Specific Antigen