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 Wang, Long. G. Articles by Ferrari, A. C. Search for Related Content PubMed PubMed Citation Articles by Wang, Long. G. Articles by Ferrari, A. C.

Overexpressed Androgen Receptor Linked to p21^WAF1 Silencing May Be Responsible for Androgen Independence and Resistance to Apoptosis of a Prostate Cancer Cell Line¹

Department of Medicine, Division of Medical Oncology and D. H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029

An androgen-independent (AI) prostate cancer cell line, derived recently from an LNCaP cell line maintained in androgen-poor conditions, has properties resembling a subgroup of advanced prostate cancers in that it has an overexpressed androgen receptor (AR), undetectable levels of p21^WAF1 and prostate-specific antigen, and is resistant to apoptosis. The loss of prostate-specific antigen expression but not the p21^WAF1 is attributable to gene silencing by hypermethylation. The high AR and undetectable p21^WAF1 of AI cells, and lower AR but highly expressed p21^WAF1 of androgen-dependent parental LNCaP cells, suggest a possibility of a functional link between these two proteins. Therefore, we examined the impact the modulation of AR will have on the expression of p21^WAF1. Treatment of androgen-dependent cells with an androgen agonist, R1881, increased the AR protein level, whereas it simultaneously reduced the endogenous p21^WAF1-protein 8-fold and the activity of a transiently transfected p21-promoter-reporter 10-fold. The down-regulation of p21^WAF1 promoter appeared to be ARE mediated, dependent on AR, and not cell-type specific. Furthermore, a reduction of the AR level in AI cells by AR-antisense oligonucleotide increased the p21^WAF1 promoter-reporter activity by 4-fold, confirming a functional link between these two proteins. A strong, direct induction of p21^WAF1 expression achieved by treatment of AI cells with trichostatin A produced a partial reversion of the AI phenotype evidenced by increased sensitivity of these cells to paclitaxel-induced apoptosis. Moreover, a reduction of AR level by antisense treatment, which also increased p21^WAF1 expression, partially restored the androgen dependence of AI cells for growth. The functional link between AR dosage and p21^WAF1 expression suggests that therapeutic reduction of AR protein in advanced prostate cancers with elevated AR levels may re-establish their hormone dependence and improve therapeutic response to repeated hormonal ablation and/or induction of apoptosis.

This article has been cited by other articles:

				L. G. Wang, E. M. Johnson, Y. Kinoshita, J. S. Babb, M. T. Buckley, L. F. Liebes, J. Melamed, X.-M. Liu, R. Kurek, L. Ossowski, et al. Androgen Receptor Overexpression in Prostate Cancer Linked to Pur{alpha} Loss from a Novel Repressor Complex Cancer Res., April 15, 2008; 68(8): 2678 - 2688. [Abstract] [Full Text] [PDF]

				S. Ko, L. Shi, S. Kim, C. S. Song, and B. Chatterjee Interplay of Nuclear Factor-{kappa}B and B-myb in the Negative Regulation of Androgen Receptor Expression by Tumor Necrosis Factor {alpha} Mol. Endocrinol., February 1, 2008; 22(2): 273 - 286. [Abstract] [Full Text] [PDF]

				R. D. Dinnen, L. Drew, D. P. Petrylak, Y. Mao, N. Cassai, J. Szmulewicz, P. Brandt-Rauf, and R. L. Fine Activation of Targeted Necrosis by a p53 Peptide: A NOVEL DEATH PATHWAY THAT CIRCUMVENTS APOPTOTIC RESISTANCE J. Biol. Chem., September 14, 2007; 282(37): 26675 - 26686. [Abstract] [Full Text] [PDF]

				J. K. Hess-Wilson, H. K. Daly, W. A. Zagorski, C. P. Montville, and K. E. Knudsen Mitogenic Action of the Androgen Receptor Sensitizes Prostate Cancer Cells to Taxane-Based Cytotoxic Insult Cancer Res., December 15, 2006; 66(24): 11998 - 12008. [Abstract] [Full Text] [PDF]

				T. Inoue, T. Yoshida, Y. Shimizu, T. Kobayashi, T. Yamasaki, Y. Toda, T. Segawa, T. Kamoto, E. Nakamura, and O. Ogawa Requirement of Androgen-Dependent Activation of Protein Kinase C{zeta} for Androgen-Dependent Cell Proliferation in LNCaP Cells and Its Roles in Transition to Androgen-Independent Cells Mol. Endocrinol., December 1, 2006; 20(12): 3053 - 3069. [Abstract] [Full Text] [PDF]

				M. M.R. Bhuiyan, Y. Li, S. Banerjee, F. Ahmed, Z. Wang, S. Ali, and F. H. Sarkar Down-regulation of Androgen Receptor by 3,3'-Diindolylmethane Contributes to Inhibition of Cell Proliferation and Induction of Apoptosis in Both Hormone-Sensitive LNCaP and Insensitive C4-2B Prostate Cancer Cells. Cancer Res., October 15, 2006; 66(20): 10064 - 10072. [Abstract] [Full Text] [PDF]

				L.G. Wang, X.M. Liu, and J.W. Chiao Repression of androgen receptor in prostate cancer cells by phenethyl isothiocyanate Carcinogenesis, October 1, 2006; 27(10): 2124 - 2132. [Abstract] [Full Text] [PDF]

				T. V. Kalin, I-C. Wang, T. J. Ackerson, M. L. Major, C. J. Detrisac, V. V. Kalinichenko, A. Lyubimov, and R. H. Costa Increased Levels of the FoxM1 Transcription Factor Accelerate Development and Progression of Prostate Carcinomas in both TRAMP and LADY Transgenic Mice Cancer Res., February 1, 2006; 66(3): 1712 - 1720. [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. Wang, H. Deng, I. Basu, and L. Zhu Induction of Androgen Receptor-Dependent Apoptosis in Prostate Cancer Cells by the Retinoblastoma Protein Cancer Res., February 15, 2004; 64(4): 1377 - 1385. [Abstract] [Full Text] [PDF]

				K. Shimada, M. Nakamura, E. Ishida, M. Kishi, and N. Konishi Roles of p38- and c-jun NH2-terminal kinase-mediated pathways in 2-methoxyestradiol-induced p53 induction and apoptosis Carcinogenesis, June 1, 2003; 24(6): 1067 - 1075. [Abstract] [Full Text] [PDF]