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 Zhao, X.-Y. Articles by Feldman, D. Search for Related Content PubMed PubMed Citation Articles by Zhao, X.-Y. Articles by Feldman, D.

Induction of Androgen Receptor by 1,25-Dihydroxyvitamin D₃ and 9-cis Retinoic Acid in LNCaP Human Prostate Cancer Cells¹

Departments of Medicine (X.-Y.Z., L.H.L., D.F.) and Urology (D.M.P.), Stanford University School of Medicine, Stanford, California 94305

Address all correspondence and requests for reprints to: David Feldman, M.D., Division of Endocrinology, Stanford University Medical Center, Room S-005, Stanford, California 94305-5103.

We have recently shown that 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] inhibits proliferation of LNCaP cells, an androgen-responsive human prostate cancer cell line. Also, 1,25-(OH)₂D₃ increases androgen receptor (AR) abundance and enhances cellular responses to androgen in these cells. In the current study, we have investigated the mechanism by which 1,25-(OH)₂D₃ regulates AR gene expression and the involvement of AR in the 1,25-(OH)₂D₃- and 9-cis retinoic acid (RA)-mediated growth inhibition of LNCaP cells. Northern blot analyses demonstrated that the steady-state messenger RNA (mRNA) level of AR was significantly increased by 1,25-(OH)₂D₃ in a dose-dependent manner. Time-course experiments revealed that the increase of AR mRNA by 1,25-(OH)₂D₃ exhibited delayed kinetics. In response to 1,25-(OH)₂D₃, AR mRNA levels were first detected to rise at 8 h and reached a maximal induction of 10-fold over the untreated control at 48 h; the effect was sustained at 72 h. Furthermore, the induction of AR mRNA by 1,25-(OH)₂D₃ was completely abolished by incubation of cells with cycloheximide, a protein synthesis inhibitor. 1,25-(OH)₂D₃ was unable to induce expression of an AR promoter-luciferase reporter. Together, these findings indicate that the stimulatory effect of 1,25-(OH)₂D₃ on AR gene expression is indirect. Western blot analyses showed an increase of AR protein in 1,25-(OH)₂D₃-treated cells. This increased expression of AR was followed by 1,25-(OH)₂D₃-induced inhibition of growth in LNCaP cells. Similar to 1,25-(OH)₂D₃, 9-cis RA also induced AR mRNA expression, and the effect of both hormones was additive. Moreover, 1,25-(OH)₂D₃ and 9-cis RA acted synergistically to inhibit LNCaP cell growth. These antiproliferative effects of 1,25-(OH)₂D₃ and 9-cis RA, alone or in combination, were blocked by the pure AR antagonist, Casodex. In conclusion, our results demonstrate that growth inhibition of LNCaP cells by 1,25-(OH)₂D₃ and 9-cis RA is mediated by an AR-dependent mechanism and preceded by the induction of AR gene expression. This finding, that differentiating agents such as vitamin D and A derivatives are potent inducers of AR, may have clinical implications in the treatment of prostate cancer.

This article has been cited by other articles:

				J. Kaeding, J. Belanger, P. Caron, M. Verreault, A. Belanger, and O. Barbier Calcitrol (1{alpha},25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells Mol. Cancer Ther., February 1, 2008; 7(2): 380 - 390. [Abstract] [Full Text] [PDF]

				T. M. Beer, M. Garzotto, B. Park, M. Mori, A. Myrthue, N. Janeba, D. Sauer, and K. Eilers Effect of Calcitriol on Prostate-Specific Antigen In vitro and in Humans. Clin. Cancer Res., May 1, 2006; 12(9): 2812 - 2816. [Abstract] [Full Text] [PDF]

				Z Culig, H Steiner, G Bartsch, and A Hobisch Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours Endocr. Relat. Cancer, June 1, 2005; 12(2): 229 - 244. [Abstract] [Full Text] [PDF]

				X.-Y. Zhao, D. Schneider, S. L. Biroc, R. Parry, B. Alicke, P. Toy, J.-A. Xuan, C. Sakamoto, K. Wada, M. Schulze, et al. Targeting Tomoregulin for Radioimmunotherapy of Prostate Cancer Cancer Res., April 1, 2005; 65(7): 2846 - 2853. [Abstract] [Full Text] [PDF]

				L. V. Stewart and N. L. Weigel Vitamin D and Prostate Cancer Experimental Biology and Medicine, April 1, 2004; 229(4): 277 - 284. [Abstract] [Full Text] [PDF]

				C. Spitzweg, I. V. Scholz, E. R. Bergert, D. J. Tindall, C. Y. F. Young, B. Goke, and J. C. Morris Retinoic Acid-Induced Stimulation of Sodium Iodide Symporter Expression and Cytotoxicity of Radioiodine in Prostate Cancer Cells Endocrinology, August 1, 2003; 144(8): 3423 - 3432. [Abstract] [Full Text] [PDF]

				D. M. Peehl, A. V. Krishnan, and D. Feldman Pathways Mediating the Growth-Inhibitory Actions of Vitamin D in Prostate Cancer J. Nutr., July 1, 2003; 133(7): 2461S - 2469. [Abstract] [Full Text] [PDF]

				S. Wilkinson and G. W. Chodak Critical Review of Complementary Therapies for Prostate Cancer J. Clin. Oncol., June 1, 2003; 21(11): 2199 - 2210. [Abstract] [Full Text] [PDF]

				A. V. Krishnan, X.-Y. Zhao, S. Swami, L. Brive, D. M. Peehl, K. R. Ely, and D. Feldman A Glucocorticoid-Responsive Mutant Androgen Receptor Exhibits Unique Ligand Specificity: Therapeutic Implications for Androgen-Independent Prostate Cancer Endocrinology, May 1, 2002; 143(5): 1889 - 1900. [Abstract] [Full Text] [PDF]

				X. Guo, B. S. Knudsen, D. M. Peehl, A. Ruiz, D. Bok, R. R. Rando, J. S. Rhim, D. M. Nanus, and L. J. Gudas Retinol Metabolism and Lecithin:Retinol Acyltransferase Levels Are Reduced in Cultured Human Prostate Cancer Cells and Tissue Specimens Cancer Res., March 1, 2002; 62(6): 1654 - 1661. [Abstract] [Full Text] [PDF]

				H.-K. Lin, S. Yeh, H.-Y. Kang, and C. Chang Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor PNAS, June 7, 2001; (2001) 121173298. [Abstract] [Full Text] [PDF]

				J. L. Martin and S. L. Pattison Insulin-Like Growth Factor Binding Protein-3 Is Regulated by Dihydrotestosterone and Stimulates Deoxyribonucleic Acid Synthesis and Cell Proliferation in LNCaP Prostate Carcinoma Cells Endocrinology, July 1, 2000; 141(7): 2401 - 2409. [Abstract] [Full Text] [PDF]

				X.-Y. Zhao, D. M. Peehl, N. M. Navone, and D. Feldman 1{alpha},25-Dihydroxyvitamin D3 Inhibits Prostate Cancer Cell Growth by Androgen-Dependent and Androgen-Independent Mechanisms Endocrinology, July 1, 2000; 141(7): 2548 - 2556. [Abstract] [Full Text] [PDF]

				T. J. Schrader and G. M. Cooke Examination of Selected Food Additives and Organochlorine Food Contaminants for Androgenic Activity in Vitro Toxicol. Sci., February 1, 2000; 53(2): 278 - 288. [Abstract] [Full Text] [PDF]

				D. Feldman, X.-Y. Zhao, and A. V. Krishnan Editorial/Mini-Review: Vitamin D and Prostate Cancer Endocrinology, January 1, 2000; 141(1): 5 - 9. [Full Text] [PDF]

				M. Guzey, S. Takayama, and J. C. Reed BAG1L Enhances Trans-activation Function of the Vitamin D Receptor J. Biol. Chem., December 22, 2000; 275(52): 40749 - 40756. [Abstract] [Full Text] [PDF]

				H.-K. Lin, S. Yeh, H.-Y. Kang, and C. Chang Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor PNAS, June 19, 2001; 98(13): 7200 - 7205. [Abstract] [Full Text] [PDF]