Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration-Resistant Prostate Cancer

Cancer Res. 2018 Jul 15;78(14):4022-4035. doi: 10.1158/0008-5472.CAN-17-3728. Epub 2018 May 15.


Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40. Pull-down studies using biotinylated-C86 found Hsp40 present in a multiprotein complex with full-length (FL-) AR, ARv7, and Hsp70 in CRPC cells. Treatment of CRPC cells with C86 or the allosteric Hsp70 inhibitor JG98 resulted in rapid protein destabilization of both FL-AR and ARv, including ARv7, concomitant with reduced FL-AR- and ARv7-mediated transcriptional activity. The glucocorticoid receptor, whose elevated expression in a subset of CRPC also leads to androgen-independent AR target gene transcription, was also destabilized by inhibition of Hsp40 or Hsp70. In vivo, Hsp40 or Hsp70 inhibition demonstrated single-agent and combinatorial activity in a 22Rv1 CRPC xenograft model. These data reveal that, in addition to recognized roles of Hsp40 and Hsp70 in FL-AR LBD remodeling, ARv lacking the LBD remain dependent on molecular chaperones for stability and function. Our findings highlight the feasibility and potential benefit of targeting the Hsp40/Hsp70 chaperone axis to treat prostate cancer that has become resistant to standard antiandrogen therapy.Significance: These findings highlight the feasibility of targeting the Hsp40/Hsp70 chaperone axis to treat CRPC that has become resistant to standard antiandrogen therapy. Cancer Res; 78(14); 4022-35. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • A549 Cells
  • Alternative Splicing / drug effects
  • Androgen Antagonists / pharmacology
  • Androgens / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • COS Cells
  • Cell Line
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • HEK293 Cells
  • HSP40 Heat-Shock Proteins / metabolism*
  • HSP70 Heat-Shock Proteins / metabolism*
  • Humans
  • Male
  • Mice, Nude
  • Molecular Chaperones / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / metabolism*
  • RNA Splicing / drug effects
  • Receptors, Androgen / metabolism*
  • Signal Transduction / drug effects
  • Transcription, Genetic / drug effects


  • Androgen Antagonists
  • Androgens
  • Antineoplastic Agents
  • DNAJB1 protein, human
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Molecular Chaperones
  • Receptors, Androgen