Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells.
Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells.
复制标题
ORAI1有助于在前列腺癌细胞中建立抗凋亡的表型。
DOI：
10.1038/cddis.2010.52
复制
发表时间：
2010-09-16
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
钙（Ca 2+）依赖性机制的分子性质和在癌细胞凋亡中具有主要作用的离子通道仍然是争论的主题。在这里，我们表明，最近确定的Orai 1蛋白代表的主要分子组成的内源性存储操作的钙离子进入（SOCE）在人前列腺癌（PCa）细胞，并构成的主要来源的Ca 2+流入的细胞触发凋亡。Orai 1的下调以及随后的SOCE保护细胞免受多种凋亡诱导途径的影响，例如毒胡萝卜素（Tg）、肿瘤坏死因子α和顺铂/奥沙利铂诱导的凋亡。将功能性Orai 1突变体如选择性突变体R91 W和卷曲螺旋突变体L273 S转染到细胞中显著降低了SOCE和TG诱导的凋亡率。这表明STIM 1与Orai 1的功能性偶联以及Orai 1作为通道的Ca 2+选择性是其促凋亡作用所需的。我们还发现雄激素非依赖性前列腺癌细胞的凋亡抵抗与Orai 1表达下调以及SOCE有关。Orai 1拯救，Orai 1转染类固醇剥夺细胞后，重新建立了存储操作的通道电流，并恢复正常的凋亡率。因此，Orai 1在触发细胞凋亡中具有关键作用，而与前列腺癌诱导刺激无关，并且在前列腺癌细胞中建立前列腺癌抗性表型。
The molecular nature of calcium (Ca2+)-dependent mechanisms and the ion channels having a major role in the apoptosis of cancer cells remain a subject of debate. Here, we show that the recently identified Orai1 protein represents the major molecular component of endogenous store-operated Ca2+ entry (SOCE) in human prostate cancer (PCa) cells, and constitutes the principal source of Ca2+ influx used by the cell to trigger apoptosis. The downregulation of Orai1, and consequently SOCE, protects the cells from diverse apoptosis-inducing pathways, such as those induced by thapsigargin (Tg), tumor necrosis factor α, and cisplatin/oxaliplatin. The transfection of functional Orai1 mutants, such as R91W, a selectivity mutant, and L273S, a coiled-coil mutant, into the cells significantly decreased both SOCE and the rate of Tg-induced apoptosis. This suggests that the functional coupling of STIM1 to Orai1, as well as Orai1 Ca2+-selectivity as a channel, is required for its pro-apoptotic effects. We have also shown that the apoptosis resistance of androgen-independent PCa cells is associated with the downregulation of Orai1 expression as well as SOCE. Orai1 rescue, following Orai1 transfection of steroid-deprived cells, re-established the store-operated channel current and restored the normal rate of apoptosis. Thus, Orai1 has a pivotal role in the triggering of apoptosis, irrespective of apoptosis-inducing stimuli, and in the establishment of an apoptosis-resistant phenotype in PCa cells.
登录
查看更多内容
影响因子：
4.8
作者：
Ng, Siaw Wei;Di Capite, Joseph;Parekh, Anant B.
通讯作者：
Parekh, Anant B.
影响因子：
5.8
作者：
Cartharius, K;Frech, K;Werner, T
通讯作者：
Werner, T
影响因子：
8
作者：
Lehen'kyi, V.;Flourakis, M.;Prevarskaya, N.
通讯作者：
Prevarskaya, N.
影响因子：
50.5
作者：
Bonkhoff, H
通讯作者：
Bonkhoff, H
影响因子：
21.3
作者：
Peinelt, Christine;Vig, Monika;Kinet, Jean-Pierre
通讯作者：
Kinet, Jean-Pierre