Hydrogen peroxide-mediated cytosolic acidification is a signal for mitochondrial translocation of Bax during drug-induced apoptosis of tumor cells
Hydrogen peroxide-mediated cytosolic acidification is a signal for mitochondrial translocation of Bax during drug-induced apoptosis of tumor cells
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DOI：
10.1158/0008-5472.can-04-0648
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发表时间：
2004-11-01
期刊：
影响因子：
11.2
通讯作者：
Pervaiz, S
中科院分区：
文献类型：
--
作者：
Ahmad, KA;Iskandar, KB;Pervaiz, S
缺乏促凋亡蛋白Bax使肿瘤细胞抵抗药物诱导的凋亡。我们已经证明过氧化氢（H2O2）介导的细胞质酸化是药物诱导肿瘤细胞凋亡的一种效应机制。在这里，我们报道Bax在确定肿瘤细胞对h2o2诱导的凋亡的敏感性方面是至关重要的。更重要的是，在药物诱导的细胞凋亡过程中，大肠癌（HCT116）和白血病细胞（HL60和CEM）暴露于H2O2或细胞内产生H2O2是Bax线粒体易位的信号。此外，我们提供的证据表明，肿瘤细胞中药物诱导的h2o2介导的Bax易位与caspase无关，但涉及细胞质酸化。抑制胞质酸化可防止Bax易位，相反，即使在没有触发因素的情况下，细胞内环境的强制酸化也会导致Bax的线粒体募集。这些发现提供了Bax线粒体易位的新机制，并直接暗示了h2o2介导的细胞质酸化在药物诱导的肿瘤细胞凋亡过程中线粒体途径的募集。
Absence of the proapoptotic protein Bax renders tumor cells resistant to drug-induced apoptosis. We have shown that hydrogen peroxide (H2O2)-mediated cytosolic acidification is an effector mechanism during drug-induced apoptosis of tumor cells. Here, we report that Bax is critical in determining the sensitivity of tumor cells to H2O2-induced apoptosis. More importantly, exposure of colorectal carcinoma (HCT116) and leukemia cells (HL60 and CEM) to H2O2 or its intracellular production during drug-induced apoptosis is a signal for mitochondrial translocation of Bax. Furthermore, we provide evidence that drug-induced H2O2-mediated Bax translocation in tumor cells is caspase independent but involves cytosolic acidification. Inhibiting cytosolic acidification prevents Bax translocation, and contrarily enforced acidification of the intracellular milieu results in mitochondrial recruitment of Bax, even in the absence of a trigger. These findings provide a novel mechanism for mitochondrial translocation of Bax and directly implicate H2O2-mediated cytosolic acidification in the recruitment of the mitochondrial pathway during drug-induced apoptosis of tumor cells.