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Androgen regulates apoptosis induced by TNFR family ligands via multiple signaling pathways in LNCaP

Oncogene volume 24, pages 6773–6784 (2005)Cite this article

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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Authors and Affiliations

  1. Department of Pathology, University of Iowa, Iowa City, 1163 ML, IA, USA

    Oskar W Rokhlin, Agshin F Taghiyev, Natalya V Guseva, Rebecca A Glover & Michael B Cohen

  2. Department of Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    Peter M Chumakov & Julia E Kravchenko

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  1. Oskar W Rokhlin
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  2. Agshin F Taghiyev
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  3. Natalya V Guseva
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  4. Rebecca A Glover
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  5. Peter M Chumakov
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  6. Julia E Kravchenko
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  7. Michael B Cohen
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Correspondence to Oskar W Rokhlin.

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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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