Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells
Open accessAbstract
Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52-enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation.
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MJC13 is predicted to target the AR BF3 surface.
“We previously demonstrated that mutations within the AR BF3 surface result in increased dependence on FKBP52 for function, and MJC13, which specifically inhibits FKBP52-regulated AR activity, is predicted to target the AR BF3 surface [13].”
From The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling (2015) · cites this paper as [13]
MJC13 specifically inhibits FKBP52-regulated AR activity.
“We previously demonstrated that mutations within the AR BF3 surface result in increased dependence on FKBP52 for function, and MJC13, which specifically inhibits FKBP52-regulated AR activity, is predicted to target the AR BF3 surface [13].”
From The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling (2015) · cites this paper as [13]
The FKBP52 cochaperone regulates AR through the BF3 surface.
“Interestingly, the FKBP52 cochaperone is thought to regulate AR through the BF3 surface [13], and our data indicate that FKBP52 directly interacts with β-catenin to promote β-catenin interaction with AR leading to a synergistic up-regulation of AR activity.”
From The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling (2015) · cites this paper as [13]
AR protein levels may be regulated by AR target genes.
“Several genes known to be regulated transcriptionally by AR were identified as hit genes, suggesting AR protein levels may be regulated by AR target genes, as has been demonstrated previously for select examples such as FKBP438.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [38]
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“However, unlike PSA, FKBP51 is a component of SHR–chaperone complexes (15) and has recently been shown to promote AR function in LNCaP cells similar to FKBP52 (16).”
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“Although FK506 binding to a similar region in FKBP52 does not result in immunosuppression, FK506 does inhibit FKBP52-mediated potentiation of SHR function (3) and the drug inhibits LNCaP prostate cancer cell proliferation (8), suggesting that interference with FKBP52 modulation of AR activity may provide a novel route…”
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FKBP51 and FKBP52 in signaling and disease
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“In addition, a series of compounds that specifically inhibit FKBP52 regulation of androgen receptor function effectively block androgen-dependent gene expression and cell proliferation in prostate cancer cells [53].”
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“Dihydrotestosterone (DHT) and MJC13 were described previously [13, 25].”
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“To investigate the mechanism by which PTGES3 regulates AR, we confirmed that repression of PTGES3 or known co-chaperones of cytosolic AR, HSP90 or FKBP4, resulted in decreased AR protein levels as expected (Extended Data Fig.”
Influential
- Authors
- De Leon, J. T., Iwai, A., Feau, C., Garcia, Y., Balsiger, H. A., Storer, C. L., Suro, R. M., Garza, K. M., Lee, S., Sang Kim, Y., Chen, Y., Ning, Y.-M., Riggs, D. L., Fletterick, R. J., Guy, R. K., Trepel, J. B., Neckers, L. M., & Cox, M. B.
- Affiliations
- Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968;
- National Institutes of Health (US)
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105;
- The University of Texas at El Paso (US)
- Medical Oncology Branch, National Cancer Institute, Bethesda, MD 20892;
- University of South Florida (US)
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993;
- Mayo Clinic in Arizona (US)
- University of California, San Francisco (US)
- St. Jude Children's Research Hospital (US)
- Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-07-05
- Volume
- 108
- Issue
- 29
- Pages
- 11878-11883
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3141981
- OpenAlex
- W2095722179
- Semantic Scholar
- 32665804922678a88a78ebb9a6d40c5a8e7c038b
- Cited by
- 132
- References
- 23
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2 · 2023: 10 · 2022: 5 · 2021: 12 · 2020: 4 · 2019: 9 · 2018: 8 · 2017: 7 · 2016: 7 · 2015: 14 · 2014: 17 · 2013: 17 · 2012: 9
- FWCI
- 13.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (0832951)
- U.S. Department of Defense (W81XWH)
- St. Jude Children's Research Hospital
- American Lebanese Syrian Associated Charities
- National Institutes of Health (W81XWH)
- National Cancer Institute
- National Institute of General Medical Sciences (SC1GM084863, R25GM069621)
- National Institute of Diabetes and Digestive and Kidney Diseases (R55DK058080, R01DK058080, DK58080)
- National Center for Research Resources (G12RR008124)
- DOD Prostate Cancer Research Program
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- androgen receptor, FKBP52, Hsp90 co-chaperone, castration-resistant prostate cancer, natural product inhibitors, androgen receptor signaling, prostate cancer cell proliferation
- MeSH terms
- Animals, beta-Galactosidase, Enzyme-Linked Immunosorbent Assay, Fluorescence, Gene Expression Regulation, Humans, Male, Models, Molecular, Prostatic Neoplasms, Receptors, Androgen, Yeasts, Immunoblotting, Molecular Structure, HSP90 Heat-Shock Proteins, Tacrolimus Binding Proteins, Cell Line, Tumor, Multiprotein Complexes, Immunoprecipitation, Cell Proliferation, Mice, Drug Discovery, Molecular Dynamics Simulation
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