[Show abstract][Hide abstract] ABSTRACT: 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.
Cell Research 10/2010; 20(10):1138-47. DOI:10.1038/cr.2010.65 · 12.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Androgen and its receptor (AR) have been reported to have pro- or antiapoptotic functions. However, the underlying molecular
mechanism is incompletely understood. We report here that androgen and AR promote Bax-mediated apoptosis in prostate cancer
cells. UV irradiation and ectopic expression of Bax induce apoptosis in AR-positive, but not AR-negative prostate cancer cells.
UV- and Bax-induced apoptosis is abrogated in AR-positive cells that express small interference RNA (siRNA) of AR and is sensitized
by reintroduction of AR into AR-negative cells. Although AR is able to promote Bax-mediated apoptosis independently of androgen,
the promotion by AR can be further potentiated by androgen via AR-dependent transcription activation. AR is essential for
the translocation of Bax to mitochondria in UV- or Bax-induced apoptosis. Inhibition of Bax expression by Bax siRNA suppresses
UV-induced apoptosis in AR-positive cells. In addition, introduction of AR into AR-negative prostate cancer cells upregulates
expression levels of the BH3-only protein Noxa, whereas inhibition of Noxa expression reduces the promotion by AR on UV-induced
apoptosis. Thus, our results reveal a novel cross talk between the androgen/AR hormonal signaling pathway and the intrinsic
apoptotic death pathway that determines the sensitivity of stress-induced apoptosis in prostate cancer cells.