ISSN: 1838-7640Theranostics
- Current issue
- Volume 14; 2024
- Volume 13; 2023
- Volume 12; 2022
- Volume 11; 2021
- Volume 10; 2020
- Archive
- Advance articles
- Cover images
- Index & coverage
- Cover suggestion
- Special issues
Nanotheranostics 2024; 8(4): 442-457. [Abstract] [Full text] [PDF]
Nanotheranostics 2024; 8(4): 427-441. [Abstract] [Full text] [PDF]
International Journal of Biological Sciences
International Journal of Medical Sciences
Global reach, higher impact
Theranostics 2021; 11(2):958-973. doi:10.7150/thno.51478 This issue Cite
Research Paper
Bruceantin targets HSP90 to overcome resistance to hormone therapy in castration-resistant prostate cancer
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
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
Citation styles
