Calmodulin protects androgen receptor from calpain-mediated breakdown in prostate cancer cells.
Calmodulin protects androgen receptor from calpain-mediated breakdown in prostate cancer cells.
复制标题
DOI：
10.1002/jcp.22516
复制
发表时间：
2011-07
影响因子：
5.6
通讯作者：
Reddy, G. Prem-Veer
中科院分区：
文献类型：
--
作者：
Sivanandam, Arun;Murthy, Shalini;Chinnakannu, Kannagi;Bai, V. Uma;Kim, Sahn-Ho;Barrack, Evelyn R.;Menon, Mani;Reddy, G. Prem-Veer
60多年来，雄激素消融术或抗雄激素治疗雄激素受体（AR）失活一直是治疗弥散性前列腺癌的一线治疗方法，但由于去势抵抗性前列腺癌细胞保留了AR活性，因此无法治愈。因此，治疗策略应包括靶向消除AR蛋白。由于AR与钙调素（CaM）结合，并且CaM结合蛋白是calpain介导的蛋白水解的靶点，因此我们研究了CaM和calpain在前列腺癌细胞中AR分解中的作用。然而，单独使用抗cam药物或钙霉素治疗前列腺癌细胞，增加细胞内钙++并激活钙蛋白酶，导致最小的AR分解，联合治疗导致AR蛋白水平急剧下降。AR蛋白的减少没有发生AR mRNA水平的明显变化，表明AR蛋白的转换增加而不是抑制AR mRNA的表达。因此，CaM失活似乎使AR对前列腺癌细胞中calpain介导的分解敏感。与这种可能性一致的是，纯化的重组人AR （rhAR）在纯化的钙蛋白酶存在下进行蛋白水解，并且在孵育过程中添加纯化的CaM阻断了rhAR蛋白水解。总之，这些观察结果表明AR是calpain的靶点，AR结合的CaM在保护AR免受calpain介导的前列腺癌细胞分解中起重要作用。这些观察结果提出了一种有趣的可能性，即抗AR药物与calpain激活剂联合使用可能为前列腺癌的治疗提供一种治疗策略，前列腺癌的生长和生存依赖于AR。
Although inactivation of the androgen receptor (AR) by androgen-ablation or anti-androgen treatment has been frontline therapy for disseminated prostate cancer for over 60 years, it is not curative because castration-resistant prostate cancer cells retain AR activity. Therefore, curative strategy should include targeted elimination of AR protein. Since AR binds to calmodulin (CaM), and since CaM-binding proteins are targets of calpain-mediated proteolysis, we studied the role of CaM and calpain in AR breakdown in prostate cancer cells. Whereas the treatment of prostate cancer cells individually with anti-CaM drug or calcimycin, which increases intracellular Ca++ and activates calpain, led to minimal AR breakdown, combined treatment led to a precipitous decrease in AR protein levels. This decrease in AR protein occurred without noticeable changes in AR mRNA levels, suggesting an increase in AR protein turnover rather than inhibition of AR mRNA expression. Thus, CaM inactivation seems to sensitize AR to calpain-mediated breakdown in prostate cancer cells. Consistent with this possibility, purified recombinant human AR (rhAR) underwent proteolysis in the presence of purified calpain, and the addition of purified CaM to the incubation blocked rhAR proteolysis. Together, these observations demonstrate that AR is a calpain target and AR-bound CaM plays an important role in protecting AR from calpain-mediated breakdown in prostate cancer cells. These observations raise an intriguing possibility that anti-CaM drugs in combination with calpain-activating agents may offer a curative strategy for the treatment of prostate cancer, which relies on AR for growth and survival.
登录
查看更多内容
影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
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：
6.6
作者：
Ford, OH;Gregory, CW;Mohler, JL
通讯作者：
Mohler, JL