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- Title
Androgen regulates apoptosis induced by TNFR family ligands via multiple signaling pathways in LNCaP.
- Authors
Rokhlin, Oskar W.; Taghiyev, Agshin F.; Guseva, Natalya V.; Glover, Rebecca A.; Chumakov, Peter M.; Kravchenko, Julia E.; Cohen, Michael B.
- 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.Oncogene (2005) 24, 6773–6784. doi:10.1038/sj.onc.1208833; published online 20 June 2005
- Subjects
ANDROGENS; APOPTOSIS; LIGANDS (Biochemistry); CANCER treatment; P53 antioncogene; P53 protein
- Publication
Oncogene, 2005, Vol 24, Issue 45, p6773
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1208833