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Departments of Surgery and Molecular Biology, Division of Urology, University of Maryland School of Medicine, Baltimore, Maryland 21201
Address all correspondence and requests for reprints to: Natasha Kyprianou, Ph.D., Division of Urology, Department Surgery, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201. E-mail: nkyprianou{at}smail.umaryland.edu
In this study, the potential interactions between dihydrotestosterone (DHT), a survival factor, and transforming growth factor-ß (TGF-ß), an apoptotic inducer, were examined in a derivative of the hormone-sensitive prostate cancer cell line LNCaP. The LNCaP TGF-ß receptor II cells, engineered to express TGF-ß receptor II, are sensitive to both DHT and TGF-ß. Surprisingly, when the LNCaP TGF-ß receptor II cells were treated with TGF-ß in the presence of physiological levels of DHT, both cell cycle arrest and apoptosis induction were significantly enhanced over TGF-ß alone. This effect temporally correlated with an increased expression of the cell cycle regulator p21 as well as the apoptotic executioner, procaspase-1, and a parallel down-regulation of the antiapoptotic protein, bcl-2. Expression of bax and caspase-3 proteins remained unchanged following treatment. Furthermore, apoptosis induction was suppressed by the caspase-1 inhibitor, z-YVAD, but not the caspase-3 inhibitor, z-DQMD, thus demonstrating the functional significance of increased procaspase-1 expression in TGF-ß-mediated apoptosis in prostate cancer cells. These results indicate that TGF-ß-mediated apoptosis can actually be enhanced by androgens through specific mechanisms involving cell cycle and apoptosis regulators and provide initial evidence on the ability of physiological levels of androgens to stimulate the intrinsic apoptotic potential of prostate cancer cells. Therefore, this study provides a molecular basis for the priming of prostate cancer cells for maximal apoptosis induction, during hormone- ablation therapy.
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