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  • Title: TGF-beta signaling and androgen receptor status determine apoptotic cross-talk in human prostate cancer cells.
    Author: Zhu ML, Partin JV, Bruckheimer EM, Strup SE, Kyprianou N.
    Journal: Prostate; 2008 Feb 15; 68(3):287-95. PubMed ID: 18163430.
    Abstract:
    BACKGROUND: A signaling interaction between transforming growth factor-beta (TGF-beta) and androgens promotes apoptosis in human prostate cancer cells LNCaP-TbetaRII (androgen-sensitive and TGF-beta responsive). This study investigated the contribution of androgen receptor (AR) in the combined effect of TGF-beta and dihydrotestosterone (DHT), on regulation of apoptosis and AR- and TGF-beta mediated transcriptional activity in human prostate cancer cells. METHODS: Transcriptional activation in response to TGF-beta (5 ng/ml) and DHT (1 nM) was evaluated using transient transfections and luciferase assays in human prostate cancer cells, LNCaP-TbetaRII and PC-3, overexpressing the wild type AR. The apoptotic response to DHT/TGFbeta treatment was correlated with AR cellular distribution and the AR interaction with TGF-beta intracellular effector Smad4. RESULTS: The results revealed that TGF-beta signaling induced AR-mediated transcriptional activation in two androgen-responsive promoters [probasin and prostate specific antigen (PSA)]. TGF-beta1 induced transcriptional activity enhanced by DHT in both cell lines (LNCaP-TbetaRII and PC-3-AR) via AR-Smad4 interaction. This interaction however does not exclusively drive TGF-beta mediated apoptosis as DHT failed to enhance such an effect in PC-3 AR (wt) cells. CONCLUSIONS: These results demonstrate that the AR status determines the sensitivity of prostate cancer cells to the apoptotic effects of TGF-beta1, thus providing a new insight into the mechanism via which TGF-beta cross-sections the AR axis toward the functional convergence of the two pathways in the development of androgen-independent prostate cancer. This study is potentially significant in defining the contribution of AR status to the emergence of androgen-independent prostate tumors.
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