Proteasomal degradation unleashes the pro-death activity of androgen receptor.
Androgen receptor (AR) is able to promote stress-induced cell death independently of its transcription activity in androgen-independent prostate cancer cells. Yet, the underlying mechanism is incompletely understood. Here, we report that stress-induced proteasomal degradation of AR contributes to its pro-death activity. Upon exposure to ultraviolet light and staurosporine, AR underwent proteasomal degradation. Blockade of AR degradation significantly suppressed stress-induced apoptosis in androgen-independent prostate cancer cells. Ectopic expression of the AR N-terminal (AR-N) domain, which lacks DNA- and ligand-binding abilities, led to cell death without any additional death stimuli. Truncation analysis revealed that AR-N domain contains several sub-domains that regulate the pro-death activity of AR, specifically the first 105 amino acids, which function as a minimal pro-death domain acting upstream of caspases. The pro-apoptotic activity of AR N-terminal fragments was suppressed by ectopic expression of Bcl-2 or selected caspase inhibitors. Thus, our results reveal a novel mechanism by which AR promotes stress-induced cell death in androgen-independent prostate cancer cells.
Godfrey
Bradley
B
Department of Biological, Chemical, and Physical Sciences, Illinois Institute of Technology, 3101 South Dearborn Street, Chicago, IL 60616, USA.
Lin
Yuting
Y
Larson
Jeffery
J
Haferkamp
Bonnie
B
Xiang
Jialing
J
D017209:Apoptosis; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013312:Stress, Physiological; D014466:Ultraviolet Rays
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; D019311:Staurosporine