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Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor

Nature Medicine volume 6, pages 703–706 (2000)Cite this article

An Erratum to this article was published on 01 August 2000

Abstract

The androgen receptor (AR) is involved in the development, growth and progression of prostate cancer1 (CaP). CaP often progresses from an androgen-dependent to an androgen-independent tumor, making androgen ablation therapy ineffective. However, the mechanisms for the development of androgen-independent CaP are unclear. More than 80% of clinically androgen-independent prostate tumors show high levels of AR expression1. In some CaPs, AR levels are increased because of gene amplification2 and/or overexpression, whereas in others, the AR is mutated3,4,5. Nonetheless, the involvement of the AR in the transition of CaP to androgen-independent growth and the subsequent failure of endocrine therapy are not fully understood. Here we show that in CaP cells from a patient who failed androgen ablation therapy, a doubly mutated AR functioned as a high-affinity cortisol/cortisone receptor (ARccr). Cortisol, the main circulating glucocorticoid, and its metabolite, cortisone, both equally stimulate the growth of these CaP cells and increase the secretion of prostate-specific antigen in the absence of androgens. The physiological concentrations of free cortisol and total cortisone in men6,7 greatly exceed the binding affinity of the ARccr and would activate the receptor, promoting CaP cell proliferation. Our data demonstrate a previously unknown mechanism for the androgen-independent growth of advanced CaP. Understanding this mechanism and recognizing the presence of glucocorticoid-responsive AR mutants are important for the development of new forms of therapy for the treatment of this subset of CaP.

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Figure 1: The doubly mutated AR shows decreased androgen binding and responsiveness.
Figure 2: The recreated AR mutants show broadened ligand specificity.
Figure 3: Glucocorticoids promote growth and secretion of PSA in MDA PCa 2b cells.

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Acknowledgements

We thank A. Hoffman and T. Stamey for critical reading of the manuscript. This work was supported by grants from the National Institutes of Health, the American Institute for Cancer Research and the US Army Medical Research Acquisition Activity (to D.F.).

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Authors and Affiliations

  1. Department of Medicine, Stanford University School of Medicine, Stanford, 94305, California, USA

    Xiao-Yan Zhao, Peter J. Malloy, Aruna V. Krishnan, Srilatha Swami & David Feldman

  2. Department of Genito-Urinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas , USA

    Nora M. Navone

  3. Department of Urology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Donna M. Peehl

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  1. Xiao-Yan Zhao
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Correspondence to David Feldman.

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Zhao, XY., Malloy, P., Krishnan, A. et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med 6, 703–706 (2000). https://doi.org/10.1038/76287

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