Androgen regulates apoptosis induced by TNFR family ligands via multiple signaling pathways in LNCaP.
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-alpha 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-alpha 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.
Rokhlin
Oskar W
OW
Department of Pathology, University of Iowa, Iowa City, 1163 ML, IA, USA. oskar-rokhlin@uiowa.edu
Taghiyev
Agshin F
AF
Guseva
Natalya V
NV
Glover
Rebecca A
RA
Chumakov
Peter M
PM
Kravchenko
Julia E
JE
Cohen
Michael B
MB
D000728:Androgens / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001483:Base Sequence; D053143:Caspase 2; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000728:Androgens; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D017931:DNA Primers; D008562:Membrane Glycoproteins; D011944:Receptors, Androgen; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D053143:Caspase 2; D020169:Caspases