Bruceantin targets HSP90 to overcome resistance to hormone therapy in castration-resistant prostate cancer

Theranostics. 2021 Jan 1;11(2):958-973. doi: 10.7150/thno.51478. eCollection 2021.

Abstract

Rationale: Aberrant androgen receptor (AR) signaling via full-length AR (AR-FL) and constitutively active AR variant 7 (AR-V7) plays a key role in the development of castration-resistant prostate cancer (CRPC) and resistance to hormone therapies. Simultaneous targeting of AR-FL and AR-V7 may be a promising strategy to overcome resistance to hormone therapy. This study aimed to identify novel drug candidates co-targeting AR-FL and AR-V7 activities and elucidate their molecular mechanism of anti-CRPC activities. Methods: Using a CRPC cell-based reporter assay system, we screened a small library of antimalarial agents to explore the possibility of repositioning them for CRPC treatment and identified bruceantin (BCT) as a potent anti-CRPC drug candidate. A series of cell-based, molecular, biochemical, and in vivo approaches were performed to evaluate the therapeutic potential and molecular mechanism of BCT in CRPC. These approaches include reporter gene assays, cell proliferation, RNA-seq, qRT-PCR, mouse xenografts, co-immunoprecipitation, GST pull-down, immobilized BCT pull-down, molecular modeling, and bioinformatic analyses. Results: We identified BCT as a highly potent inhibitor co-targeting AR-FL and AR-V7 activity. BCT inhibits the transcriptional activity of AR-FL/AR-V7 and downregulates their target genes in CRPC cells. In addition, BCT efficiently suppresses tumor growth and metastasis of CRPC cells. Mechanistically, BCT disrupts the interaction of HSP90 with AR-FL/AR-V7 by directly binding to HSP90 and inhibits HSP90 chaperone function, leading to degradation of AR-FL/AR-V7 through the ubiquitin-proteasome system. Clinically, HSP90 expression is upregulated and correlated with AR/AR-V7 levels in CRPC. Conclusion: Our findings suggest that BCT could serve as a promising therapeutic candidate against CRPC and highlight the potential benefit of targeting AR-FL/AR-V7-HSP90 axis to overcome resistance caused by aberrant AR-FL/AR-V7 signaling.

Keywords: HSP90; androgen receptor; androgen receptor variant 7; bruceantin; castration-resistant prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Receptor Antagonists / pharmacology*
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Proliferation
  • Drug Resistance, Neoplasm*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Quassins / pharmacology*
  • Receptors, Androgen / chemistry*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • AR protein, human
  • Androgen Receptor Antagonists
  • Biomarkers, Tumor
  • HSP90 Heat-Shock Proteins
  • Quassins
  • Receptors, Androgen
  • bruceantin