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

• Published in: Theranostics 2021-01, Vol.11 (2), p.958-973
• Main Authors: Moon, Sue Jin, Jeong, Byong Chang, Kim, Hwa Jin, Lim, Joung Eun, Kim, Hye-Jeong, Kwon, Ghee Young, Jackman, Joshua A, Kim, Jeong Hoon
• Format: Article
• Language: English
• Subjects: Androgens; Bioluminescence; Endocrine therapy; Experiments; Gene expression; Laboratory animals; Ligands; Malaria; Medical prognosis; Metastasis; Prostate cancer; Proteins; Research Paper; Transcription factors
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.51478

Aberrant androgen receptor (AR) signaling 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. 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. 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. 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.