This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, Y.-F. Articles by Chang, C. Search for Related Content PubMed PubMed Citation Articles by Lee, Y.-F. Articles by Chang, C.

Activation of Mitogen-activated Protein Kinase Pathway by the Antiandrogen Hydroxyflutamide in Androgen Receptor-negative Prostate Cancer Cells¹

George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Cancer Center, University of Rochester Medical Center, Rochester, New York 14642 [Y-F. L., W-J. L., J. H., E. M. M., C. C]; The Chinese University of Hong Kong, Shatin, Hong Kong, China [F.L.C.]; and University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792 [G. W.]

Whereas hydroxyflutamide (HF) has been used as an antiandrogen to block androgen-stimulated prostate tumor growth, the antiandrogen withdrawal syndrome that allows antiandrogens to stimulate prostate tumor growth still occurs in many patients treated with androgen ablation therapy. This was previously explained by mutations in the androgen receptor (AR) and/or modulation from AR coregulators, so that HF becomes an AR agonist. Using immunohistochemical analysis, we analyzed four prostate cancer patients undergoing androgen ablation therapy with flutamide and compared their phospho-extracellular signal-regulated kinase 1/2 levels in prostate cancer biopsies before receiving HF and after experiencing disease progression while taking HF. We found a significant increase of activated mitogen-activated protein (MAP) kinase in prostate tumors from patients receiving HF during androgen ablation therapy. In vitro studies showed that HF induced a rapid activation of the Ras/MAP kinase pathway in human prostate cancer DU145 cells which lack the AR, as well as in PC-3AR2 and CWR22 cells which express the AR. Cycloheximide failed to inhibit this activation, but both AG1478, an inhibitor of the epidermal growth factor receptor (EGF-R), and an EGF-R-neutralizing antibody blocked this HF-mediated activation of MAP kinase, which suggests that the activation of Ras/MAP kinase by HF is a membrane-initiated, non-AR-mediated, and nongenomic action. The consequence of this activation may result in increasing cell proliferation and cyclin D1 expression. This raises a concern for using HF in the complete-androgen-ablation therapy in prostate cancer treatment and provides a possible pathway that might contribute to the HF withdrawal syndrome.

This article has been cited by other articles:

				Y.-H. Sun, X. Gao, Y.-J. Tang, C.-L. Xu, and L.-H. Wang Androgens Induce Increases in Intracellular Calcium Via a G Protein-Coupled Receptor in LNCaP Prostate Cancer Cells J Androl, September 1, 2006; 27(5): 671 - 678. [Abstract] [Full Text] [PDF]

				N. J. MacLusky, T. Hajszan, J. A. Johansen, C. L. Jordan, and C. Leranth Androgen Effects on Hippocampal CA1 Spine Synapse Numbers Are Retained in Tfm Male Rats with Defective Androgen Receptors Endocrinology, May 1, 2006; 147(5): 2392 - 2398. [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]

				J. Huang, J. L. Yao, L. Zhang, P. A. Bourne, A. M. Quinn, P. A. di Sant'Agnese, and J. E. Reeder Differential Expression of Interleukin-8 and Its Receptors in the Neuroendocrine and Non-Neuroendocrine Compartments of Prostate Cancer Am. J. Pathol., June 1, 2005; 166(6): 1807 - 1815. [Abstract] [Full Text] [PDF]

				N. J. MacLusky, T. Hajszan, and C. Leranth Effects of Dehydroepiandrosterone and Flutamide on Hippocampal CA1 Spine Synapse Density in Male and Female Rats: Implications for the Role of Androgens in Maintenance of Hippocampal Structure Endocrinology, September 1, 2004; 145(9): 4154 - 4161. [Abstract] [Full Text] [PDF]

				C. A. Heinlein and C. Chang Androgen Receptor in Prostate Cancer Endocr. Rev., April 1, 2004; 25(2): 276 - 308. [Abstract] [Full Text] [PDF]

				M. Fu, M. Rao, C. Wang, T. Sakamaki, J. Wang, D. Di Vizio, X. Zhang, C. Albanese, S. Balk, C. Chang, et al. Acetylation of Androgen Receptor Enhances Coactivator Binding and Promotes Prostate Cancer Cell Growth Mol. Cell. Biol., December 1, 2003; 23(23): 8563 - 8575. [Abstract] [Full Text] [PDF]

				G. Sathya, C.-y. Chang, D. Kazmin, C. E. Cook, and D. P. McDonnell Pharmacological Uncoupling of Androgen Receptor-mediated Prostate Cancer Cell Proliferation and Prostate-specific Antigen Secretion Cancer Res., November 15, 2003; 63(22): 8029 - 8036. [Abstract] [Full Text] [PDF]