This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krishnan, A. V. Articles by Feldman, D. Search for Related Content PubMed PubMed Citation Articles by Krishnan, A. V. Articles by Feldman, D.

A Glucocorticoid-Responsive Mutant Androgen Receptor Exhibits Unique Ligand Specificity: Therapeutic Implications for Androgen-Independent Prostate Cancer

Departments of Medicine (A.V.K., X.-Y.Z., S.S., D.F.) and Urology (D.M.P.), Stanford University School of Medicine, Stanford, California 94305; and The Burnham Institute (L.B., K.R.E.), La Jolla, California 92037

Address all correspondence and requests for reprints to: Dr. David Feldman, Division of Endocrinology, SUMC, Room S-005, Stanford University School of Medicine, Stanford, California 94305-5103. E-mail: . feldman{at}cmgm.stanford.edu

The cortisol/cortisone-responsive AR (AR^ccr) has two mutations (L701H and T877A) that were found in the MDA PCa human prostate cancer cell lines established from a castrated patient whose metastatic tumor exhibited androgen-independent growth. Cortisol and cortisone bind to the AR^ccr with high affinity. In the present study, we characterized the structural determinants for ligand binding to the AR^ccr. Our data revealed that many of the C17, C19, and C21 circulating steroids, at concentrations that are found in vivo, functioned as effective activators of the AR^ccr but had little or no activity via the wild-type AR or GR. Among the synthetic glucocorticoids tested, dexamethasone activated both GR and AR^ccr, whereas triamcinolone was selective for GR. In MDA PCa 2b cells, growth and prostate-specific antigen production were stimulated by potent AR^ccr agonists such as cortisol or 9-fluorocortisol but not by triamcinolone (which did not bind to or activate the AR^ccr). Of the potential antagonists tested, bicalutamide (casodex) and GR antagonist RU38486 showed inhibitory activity. We postulate that corticosteroids provide a growth advantage to prostate cancer cells harboring the promiscuous AR^ccr in androgen-ablated patients and contribute to their transition to androgen-independence. We predict that triamcinolone, a commonly prescribed glucocorticoid, would be a successful therapeutic agent for men with this form of cancer, perhaps in conjunction with the antagonist casodex. We hypothesize that triamcinolone administration would inhibit the hypothalamic-pituitary-adrenal axis, thus suppressing endogenous corticosteroids, which stimulate tumor growth. Triamcinolone, by itself, would not activate the AR^ccr or promote tumor growth but would provide glucocorticoid activity essential for survival.

This article has been cited by other articles:

				A. Yemelyanov, J. Czwornog, L. Gera, S. Joshi, R. T. Chatterton Jr., and I. Budunova Novel Steroid Receptor Phyto-Modulator Compound A Inhibits Growth and Survival of Prostate Cancer Cells Cancer Res., June 15, 2008; 68(12): 4763 - 4773. [Abstract] [Full Text] [PDF]

				W. H. Bisson, A. V. Cheltsov, N. Bruey-Sedano, B. Lin, J. Chen, N. Goldberger, L. T. May, A. Christopoulos, J. T. Dalton, P. M. Sexton, et al. Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs PNAS, July 17, 2007; 104(29): 11927 - 11932. [Abstract] [Full Text] [PDF]

				H. Fazelinia, P. C. Cirino, and C. D. Maranas Extending Iterative Protein Redesign and Optimization (IPRO) in Protein Library Design for Ligand Specificity Biophys. J., March 15, 2007; 92(6): 2120 - 2130. [Abstract] [Full Text] [PDF]

				R. S. Bhattacharyya, A. V. Krishnan, S. Swami, and D. Feldman Fulvestrant (ICI 182,780) down-regulates androgen receptor expression and diminishes androgenic responses in LNCaP human prostate cancer cells. Mol. Cancer Ther., June 1, 2006; 5(6): 1539 - 1549. [Abstract] [Full Text] [PDF]

				B. He, R. T. Gampe Jr., A. T. Hnat, J. L. Faggart, J. T. Minges, F. S. French, and E. M. Wilson Probing the Functional Link between Androgen Receptor Coactivator and Ligand-binding Sites in Prostate Cancer and Androgen Insensitivity J. Biol. Chem., March 10, 2006; 281(10): 6648 - 6663. [Abstract] [Full Text] [PDF]

				E. Unni, S. Sun, B. Nan, M. J. McPhaul, B. Cheskis, M. A. Mancini, and M. Marcelli Changes in Androgen Receptor Nongenotropic Signaling Correlate with Transition of LNCaP Cells to Androgen Independence Cancer Res., October 1, 2004; 64(19): 7156 - 7168. [Abstract] [Full Text] [PDF]

				C. N. Papandreou and C. J. Logothetis Bortezomib as a Potential Treatment for Prostate Cancer Cancer Res., August 1, 2004; 64(15): 5036 - 5043. [Abstract] [Full Text] [PDF]

				M. Rahman, H. Miyamoto, and C. Chang Androgen Receptor Coregulators in Prostate Cancer: Mechanisms and Clinical Implications Clin. Cancer Res., April 1, 2004; 10(7): 2208 - 2219. [Full Text] [PDF]