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 Hess-Wilson, J. K. Articles by Knudsen, K. E. Search for Related Content PubMed PubMed Citation Articles by Hess-Wilson, J. K. Articles by Knudsen, K. E.

Mitogenic Action of the Androgen Receptor Sensitizes Prostate Cancer Cells to Taxane-Based Cytotoxic Insult

Departments of ¹ Cell Biology, ² Surgery, and ³ Obstetrics and Gynecology, ⁴ Center for Environmental Genetics, and ⁵ University of Cincinnati Cancer Center, University of Cincinnati College of Medicine, Cincinnati, Ohio

Requests for reprints: Karen E. Knudsen, Department of Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, 3125 Eden Avenue, ML 0521, Cincinnati, OH 45267-0521. Phone: 513-558-7371; Fax: 513-558-4454; E-mail: Karen.Knudsen{at}uc.edu.

Prostate cancer cells are dependent on androgen for growth and survival; as such, inhibition of androgen receptor (AR) activity is the first line of intervention for disseminated disease. Recently, specific cytotoxic agents have been shown to extend survival times in patients with advanced disease. Given the established ability of androgen to modify cell survival in prostate cancer cells, it is imperative to determine the effect of the hormonal environment on cytotoxic response. Here, we show that the response of prostate cancer cells to taxane-induced cell death is significantly enhanced by androgen stimulation in AR-positive, androgen-dependent prostate cancer cells. Similar results were observed on androgen-independent AR activation. By contrast, AR-positive yet androgen-independent or AR-negative cells were refractory to androgen influence on taxane function. The ability of androgen to potentiate taxane activity was dependent on its mitogenic capacity and was separable from overall AR activity, as coadministration of AR antagonists, G₁ cyclin-dependent kinase inhibitors, or high-dose (growth inhibitory) androgen nullified the proapoptotic function of androgen. Observed induction of cell death was attributed to caspase-dependent apoptosis and correlated with p53 activation. Combined, these data indicate that the cytotoxic effects of taxanes are substantially influenced by the hormonal environment and/or status of AR activity in prostate cancer cells and provide the foundation for refinement and optimization of cytotoxic intervention in prostate cancer. (Cancer Res 2006; 66(24): 11998-2008)

This article has been cited by other articles:

				D. Rathkopf, M. A. Carducci, M. J. Morris, S. F. Slovin, M. A. Eisenberger, R. Pili, S. R. Denmeade, M. Kelsen, T. Curley, M. Halter, et al. Phase II Trial of Docetaxel With Rapid Androgen Cycling for Progressive Noncastrate Prostate Cancer J. Clin. Oncol., June 20, 2008; 26(18): 2959 - 2965. [Abstract] [Full Text] [PDF]

				A. Sharma, C. E.S. Comstock, E. S. Knudsen, K. H. Cao, J. K. Hess-Wilson, L. M. Morey, J. Barrera, and K. E. Knudsen Retinoblastoma Tumor Suppressor Status Is a Critical Determinant of Therapeutic Response in Prostate Cancer Cells Cancer Res., July 1, 2007; 67(13): 6192 - 6203. [Abstract] [Full Text] [PDF]