Androgen deprivation therapy （ADT）, which aims to reduce androgen-androgen receptor （AR） signaling, is the normal method of prostate cancer treatment. Despite its early success in suppressing prostate tumor growth...Androgen deprivation therapy （ADT）, which aims to reduce androgen-androgen receptor （AR） signaling, is the normal method of prostate cancer treatment. Despite its early success in suppressing prostate tumor growth, the therapy eventually fails, leading to recurrent hormone-refractory tumor growth. Recent studies have been carried out with stromal cell-specific or fibroblastspecific AR knockout mice or prostate stromal-specific and epithelial-specific AR knockout transgenic mice prostate cancer models and in vitro and in vivo studies of various human prostate cancer cells with knock-in and knock-out of the AR. These have indicated that the AR in prostatic stroma acts as a proliferation stimulator and survival factor, whereas epithelial AR acts as a survival factor for epithelial luminal cells and stromal smooth muscle cell differentiation, and as a suppressor for epithelial basal intermediate cell proliferation. These two opposite AR pose a major challenge for roles of the stromal and epithelial ADT and should be taken into account when developing new therapies targeting AR in selective cells.展开更多
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...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 ul- traviolet fight 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 stressinduced cell death in androgen-independent prostate cancer cells.展开更多
文摘Androgen deprivation therapy （ADT）, which aims to reduce androgen-androgen receptor （AR） signaling, is the normal method of prostate cancer treatment. Despite its early success in suppressing prostate tumor growth, the therapy eventually fails, leading to recurrent hormone-refractory tumor growth. Recent studies have been carried out with stromal cell-specific or fibroblastspecific AR knockout mice or prostate stromal-specific and epithelial-specific AR knockout transgenic mice prostate cancer models and in vitro and in vivo studies of various human prostate cancer cells with knock-in and knock-out of the AR. These have indicated that the AR in prostatic stroma acts as a proliferation stimulator and survival factor, whereas epithelial AR acts as a survival factor for epithelial luminal cells and stromal smooth muscle cell differentiation, and as a suppressor for epithelial basal intermediate cell proliferation. These two opposite AR pose a major challenge for roles of the stromal and epithelial ADT and should be taken into account when developing new therapies targeting AR in selective cells.
文摘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 ul- traviolet fight 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 stressinduced cell death in androgen-independent prostate cancer cells.
