Abstract
It has been suggested in many studies that combined treatment with chemotherapeutic agents and apoptosis-inducing ligands belonging to TNFR family is a more effective strategy for cancer treatment. However, the role of androgen regulation of TNFR family-induced apoptosis in prostate cancer is poorly understood. In this study, we investigated the dose-dependent effects of androgen on TNF-α and TRAIL-mediated apoptosis in LNCaP. To investigate the interaction between the androgen receptor (AR) and the caspase-2 gene, chromatin immunoprecipitation analysis was used, and we are the first to identify that AR interacts in vivo with an androgen-responsive elements in intron 8 of caspase-2 gene. We have found that DHT inhibited apoptosis in dose-dependent manner. There is a direct, androgen-dependent correlation between the levels of activated Akt and caspase activation after treatment with TNF-α and TRAIL. We have also found that there are at least two different regulatory mechanisms of p53 expression by androgen: at the gene and protein levels. At the same time, the level of AR was found to be higher in LNCaP-si-p53 compared to LNCaP-mock cells. These data indicate that there is a mutual regulation of expression between p53 and AR. Our study suggests that androgen-dependent outcome of apoptotic treatment can occur, at least in part, via the caspase-2, Akt and p53-mediated pathways.
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Acknowledgements
We thank Y Lazebnik (Cold Spring Harbor Lab) for monoclonal and polyclonal antibodies to caspase-2 and the expression vector with mutated caspase-2. We thank TJ Brown (The University of Toronto, Canada) for the PC-3(AR)2 cell line and expression vector pCEP4/hAR. This work is supported by NIH Grant CA 87717.
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Rokhlin, O., Taghiyev, A., Guseva, N. et al. Androgen regulates apoptosis induced by TNFR family ligands via multiple signaling pathways in LNCaP. Oncogene 24, 6773–6784 (2005). https://doi.org/10.1038/sj.onc.1208833
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DOI: https://doi.org/10.1038/sj.onc.1208833
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