Theranostics 2021; 11(2):958-973. doi:10.7150/thno.51478 This issue

Research Paper

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

Sue Jin Moon1,2, Byong Chang Jeong3, Hwa Jin Kim1,2, Joung Eun Lim3, Hye-Jeong Kim4, Ghee Young Kwon5, Joshua A. Jackman6, Jeong Hoon Kim1,2✉

1. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, Korea
2. Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, 06351, Korea
3. Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
4. C&C Research Laboratories, Sungkyunkwan University, Suwon, 16419, Korea
5. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
6. School of Chemical Engineering and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, Korea

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Citation:
Moon SJ, Jeong BC, Kim HJ, Lim JE, Kim HJ, Kwon GY, Jackman JA, Kim JH. Bruceantin targets HSP90 to overcome resistance to hormone therapy in castration-resistant prostate cancer. Theranostics 2021; 11(2):958-973. doi:10.7150/thno.51478. Available from https://www.thno.org/v11p0958.htm

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Abstract

Graphic 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: castration-resistant prostate cancer, androgen receptor, androgen receptor variant 7, bruceantin, HSP90