Calpain-mediated androgen receptor breakdown in apoptotic prostate cancer cells.
Calpain-mediated androgen receptor breakdown in apoptotic prostate cancer cells.
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DOI：
10.1002/jcp.21565
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发表时间：
2008-12
影响因子：
5.6
通讯作者：
Dou, Q. Ping
中科院分区：
文献类型：
--
作者：
Yang, Huanjie;Murthy, Shalini;Sarkar, Fazlul H.;Sheng, Shijie;Reddy, G. Prem-Veer;Dou, Q. Ping
由于雄激素受体(AR)在前列腺癌的发生发展中起着重要作用，雄激素消融治疗已成为治疗晚期前列腺癌的一线治疗方法，尽管其治疗效果并不理想。治疗策略应该包括从功能和结构上消除前列腺癌细胞中的AR。我们以前曾报道，药物蛋白酶体抑制化合物雷公藤红素诱导的细胞凋亡与AR蛋白水平的降低有关。然而，雷公藤红素刺激的事件导致AR降低的机制尚未阐明。在此，我们报道了多种化疗药物，包括蛋白酶体抑制剂、拓扑异构酶抑制剂、DNA损伤剂和导致细胞死亡的多西紫杉醇，降低了LNCaP前列腺癌细胞的AR水平。这种AR蛋白水平的下降并不是由于这些细胞中AR mRNA的表达受到抑制。我们观察到，前列腺癌细胞胞浆中的蛋白水解酶活性是AR分解的原因，并且这种蛋白水解酶活性在诱导细胞凋亡时被激发。有趣的是，蛋白酶体抑制剂雷公藤红素和化疗药物VP-16刺激的AR分解可被钙蛋白酶抑制剂Calastatin和N-乙酰-L-亮氨酰-L-亮氨酰-L-蛋氨酸减弱。此外，钙调素-琼脂糖珠从雷公藤红素处理的PC-3细胞中拉下的AR蛋白水解酶活性显示出对Calain抗体的免疫反应。综上所述，这些结果表明，Calain参与了蛋白酶体抑制剂诱导的AR的破坏，并表明AR的降解是诱导前列腺癌细胞凋亡的内在机制。
Since androgen receptor (AR) plays an important role in prostate cancer development and progression, androgen-ablation has been the frontline therapy for treatment of advanced prostate cancer even though it is rarely curative. A curative strategy should involve functional and structural elimination of AR from prostate cancer cells. We have previously reported that apoptosis induced by medicinal proteasome-inhibitory compound celastrol is associated with a decrease in AR protein levels. However celastrol-stimulated events contributing to this AR decrease have not been elucidated. Here, we report that a variety of chemotherapeutic agents, including proteasome inhibitors, a topoisomerase inhibitor, DNA–damaging agents and docetaxel that cause cell death, decrease AR levels in LNCaP prostate cancer cells. This decrease in AR protein levels was not due to the suppression of AR mRNA expression in these cells. We observed that a proteolytic activity residing in cytosol of prostate cancer cells is responsible for AR breakdown and that this proteolytic activity was stimulated upon induction of apoptosis. Interestingly, proteasome inhibitor celastrol- and chemotherapeutic drug VP-16-stimulated AR breakdown was attenuated by calpain inhibitors calpastatin and N-Acetyl-L-leucyl-L-leucyl-L-methioninal. Furthermore, AR proteolytic activity pulled down by calmodulin-agarose beads from celastrol-treated PC-3 cells showed immunoreactivity to a calpain antibody. Taken together, these results demonstrate calpain involvement in proteasome inhibitor-induced AR breakdown, and suggest that AR degradation is intrinsic to the induction of apoptosis in prostate cancer cells.
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影响因子：
11.2
作者：
Chen, Di;Cui, Qiuzhi Cindy;Dou, Q. Ping
通讯作者：
Dou, Q. Ping
DOI：
10.1016/0022-4731(87)90117-8
发表时间：
1987-07-01
影响因子：
4.1
作者：
DEBOER, W;BOLT, J;MULDER, E
通讯作者：
MULDER, E
DOI：
10.1006/bbrc.1998.9624
发表时间：
1998-11-09
影响因子：
3.1
作者：
Kobayashi, Y;Miwa, S;Sobue, G
通讯作者：
Sobue, G
影响因子：
11.4
作者：
Lin, HK;Wang, L;Chang, CS
通讯作者：
Chang, CS
影响因子：
1.8
作者：
Culig, Z
通讯作者：
Culig, Z