Abstract
Background:
Abiraterone acetate (AA), a highly potent CYP17A1 inhibitor, has demonstrated marked clinical benefit in patients with metastatic castration-resistant prostate cancer (CRPC). Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations. The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor (AR) activity in prostate cancer (PC) cells.
Methods:
Fluorescence resonance energy transfer (FRET) assay was used to assess the effect of mineralocorticoids on androgen-induced conformational change of the AR. LAPC4, LNCaP and LN-AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations, including levels measured in the serum of AA-treated patients in a phase I trial. AR-dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells.
Results:
Corticosterone (CS) and deoxycorticosterone (DOC) inhibited androgen-induced conformational change of the AR in the FRET assay. CS inhibited AR-dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA-treated patients. DOC inhibited AR transcriptional activity and cell growth at 10-fold greater concentrations than measured in the serum of AA-treated patients.
Conclusions:
Mineralocorticoids directly inhibit androgen-induced conformational change of the AR. CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA. Further investigation of the potential therapeutic implications of mineralocorticoids in AA-treated CRPC patients is warranted.
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Acknowledgements
The authors thank Dr Charles Sawyers for his generous gift of the LAPC4 and LN-AR cells, and Dr Ingo Mellinhoff for his generous gift of bicalutamide. JOJ was supported by NIH F32 CA123750. MD was supported by NCI CA131226. CJR was supported by K23 CA115775.
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AM is an employee of Johnson & Johnson and holds stock ownership. CH is a former employee of Johnson & Johnson and holds stock ownership. CJR has received honoraria from Janssen. JM is a member of the NCCN's Prostate Cancer Early Detection Panel and, on behalf of the NCCN, has received honoraria only for lectures (usually annual meeting for guidelines update and occasional CME activity) or other activities (panel participation for guidelines adaptation for other countries); has received an honorarium from the Genomic Health Scientific Advisory Board (related activity: presentation (no honorarium), collaboration with the North Carolina-Louisiana Prostate Cancer Project (no funded effort or honorarium)); is a cofounder and chief medical officer of AndroBioSys, with ownership interest (value: none); is associated with Medivation MTA for MDV3100 (no research support or honoraria); is a consultant to and collaborator on research at New York University School of Medicine; and was an initial investor (value: none) in and an advisory board member for Simulated Surgical Systems. The remaining authors declare no conflict of interest.
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Kim, W., Jones, J., Diamond, M. et al. Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate. Prostate Cancer Prostatic Dis 17, 292–299 (2014). https://doi.org/10.1038/pcan.2014.27
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DOI: https://doi.org/10.1038/pcan.2014.27