title: Dihydrotestosterone enhances transforming growth factor-beta-induced apoptosis in hormone-sensitive prostate cancer cells.
abstract: In this study, the potential interactions between dihydrotestosterone (DHT), a survival factor, and transforming growth factor-beta (TGF-beta), an apoptotic inducer, were examined in a derivative of the hormone-sensitive prostate cancer cell line LNCAP: The LNCaP TGF-beta receptor II cells, engineered to express TGF-beta receptor II, are sensitive to both DHT and TGF-beta. Surprisingly, when the LNCaP TGF-beta receptor II cells were treated with TGF-beta in the presence of physiological levels of DHT, both cell cycle arrest and apoptosis induction were significantly enhanced over TGF-beta 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-beta-mediated apoptosis in prostate cancer cells. These results indicate that TGF-beta-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.
authors.affiliation: Department of Surgery and Molecular Biology, Division of Urology, University of Maryland School of Medicine, Baltimore 21201, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Bruckheimer
authors.forename: N
authors.initials: N
authors.lastname: Kyprianou
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: C493956:CDKN1A protein, human; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D013196:Dihydrotestosterone; D050760:Cyclin-Dependent Kinase Inhibitor p27; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases