Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death
Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death
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DOI：
10.1038/onc.2008.63
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发表时间：
2008-07-01
期刊：
影响因子：
8
通讯作者：
Kroemer, G.
中科院分区：
文献类型：
--
作者：
Tajeddine, N.;Galluzzi, L.;Kroemer, G.
在筛选了一组靶向凋亡机制各种组分的不同小干扰RNA后，我们发现敲低电压依赖性阴离子通道1（VDAC 1）在预防非小细胞肺癌细胞中顺铂（CDDP）诱导的细胞死亡方面特别有效。VDAC 1的下调和4，4 '-二异硫氰基芪-2，2'-二磺酸的化学抑制都减少了与糖尿病相关的modi。CDDP诱导的线粒体膜电位耗散和质膜透化。VDAC 1抑制强烈降低CDDP诱导的Bax构象激活，但对巴克的激活没有明显影响，表明VDAC 1作用于巴克的下游和Bax的上游。因此，巴克的敲低取消了Bax的激活，而Bax下调对巴克激活没有影响。在VDAC 1耗尽的细胞中，CDDP激活Bax的失败可以通过Bcl-2/Bcl-XL拮抗剂ABT-737逆转，其同时恢复CDDP的细胞毒性。总之，这些结果描绘了一个新的途径诱导线粒体膜透化（MMP）的过程中CDDP诱导的细胞死亡，涉及一个层次的贡献巴克，VDAC 1和Bax。此外，我们的数据表明，VDAC 1可能作为一个兼性调节/效应的MMP，这取决于初始的细胞毒性事件。
Following the screening of a battery of distinct small-interfering RNAs that target various components of the apoptotic machinery, we found that knockdown of the voltage-dependent anion channel 1 (VDAC1) was particularly efficient in preventing cell death induced by cisplatin (CDDP) in non-small cell lung cancer cells. Both the downregulation of VDAC1 and its chemical inhibition with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid reduced the apoptosis-associated modi. cations induced by CDDP, including mitochondrial transmembrane potential dissipation and plasma membrane permeabilization. VDAC1 inhibition strongly reduced the CDDP-induced conformational activation of Bax, yet had no discernible effect on the activation of Bak, suggesting that VDAC1 acts downstream of Bak and upstream of Bax. Accordingly, knockdown of Bak abolished the activation of Bax, whereas Bax downregulation had no effect on Bak activation. In VDAC1-depleted cells, the failure of CDDP to activate Bax could be reversed by means of the Bcl-2/Bcl-XL antagonist ABT-737, which concomitantly restored CDDP cytotoxicity. Altogether, these results delineate a novel pathway for the induction of mitochondrial membrane permeabilization (MMP) in the course of CDDP-induced cell death that involves a hierarchical contribution of Bak, VDAC1 and Bax. Moreover, our data suggest that VDAC1 may act as a facultative regulator/effector of MMP, depending on the initial cytotoxic event.