The role of p38 MAPK and JNK in arsenic trioxide-induced mitochondrial cell death in human cervical cancer cells
The role of p38 MAPK and JNK in arsenic trioxide-induced mitochondrial cell death in human cervical cancer cells
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DOI：
10.1002/jcp.21470
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发表时间：
2008-10-01
影响因子：
5.6
通讯作者：
Lee, Su-Jae
中科院分区：
文献类型：
--
作者：
Kang, Young-Hee;Lee, Su-Jae
以前，我们已经表明，AIF从线粒体的释放是AS（2）O（3）诱导的人宫颈癌细胞死亡所必需的，活性氧（ROS）是AIF从线粒体释放所必需的。在这项研究中，我们进一步调查的作用，MAPKs在ROS介导的线粒体凋亡细胞死亡引发的As 2 O3。AS（2）O（3）诱导的HeLa细胞凋亡与Bax的激活和线粒体转位、Bcl-2的磷酸化、Bcl-2和Bax相互作用的减少、线粒体膜电位的降低有关。使用小干扰RNA，减少Bax表达有效地减弱AS（2）O（3）诱导的线粒体膜电位损失和凋亡细胞死亡。此外，AS（2）O（3）诱导的Bcl-2磷酸化降低了其与Bax结合的能力。用AS 203处理细胞激活p38 MAPK和JNK途径。在p38 MAPK抑制剂PD 169316或si-p38 MAPK的存在下，Bax的线粒体易位被完全抑制。用SP 600125或si-JNK抑制JNK，在一定程度上用PD 169316或si-p38 MAPK抑制p38 MAPK，可减弱AS（2）O（3）诱导的Bcl-2磷酸化。此外，N-乙酰-L-半胱氨酸（NAC），一种含巯基的抗氧化剂，完全阻断AS（2）O（3）-包括p38 MAPK和JNK的激活，Bax的线粒体易位和Bcl-2的磷酸化。这些结果支持了这样的观点，即响应于AS 203处理的ROS介导的p38 MAPK和JNK的激活信号Bax的激活和Bcl-2的磷酸化，导致人宫颈癌细胞中的线粒体凋亡性细胞死亡。
Previously, we have shown that the release of AIF from mitochondria is required for AS(2)O(3)-induced cell death in human cervical cancer cells, and that reactive oxygen species (ROS) is necessary for AIF release from mitochondria. In this study, we further investigated the role of MAPKs in ROS-mediated mitochondrial apoptotic cell death triggered by As2O3. AS(2)O(3)-induced apoptotic cell death in HeLa cells was associated with activation and mitochondrial translocation of Bax, a marked phosphorylation of Bcl-2, reduction of Bcl-2 and Bax interaction, dissipation of mitochondrial membrane potential. Using small interfering RNA, reduced Bax expression effectively attenuated AS(2)O(3)-induced mitochondrial membrane potential loss and apoptotic cell death. Moreover, the phosphorylation of Bcl-2 induced by AS(2)O(3) diminished its ability to bind to Bax. Treatment of cells with AS203 activated both the p38 MAPK and JNK pathways. Mitochondrial translocation of Bax was completely suppressed in the presence of p38 MAPK inhibitor PD169316 or si-p38 MAPK. The AS(2)O(3)-induced Bcl-2 phosphorylation was attenuated largely by JNK inhibition using SP600125 or si-JNK and to some extent by p38 MAPK inhibition with PD169316 or si-p38 MAPK. In addition, N-acetyl-L-cystein (NAC), a thiol-containing anti-oxidant, completely blocked AS(2)O(3)-incluced p38 MAPK and JNK activations, mitochondria translocation of Bax, and phosphorylation of Bcl-2. These results support a notion that ROS-mediated activations of p38 MAPK and JNK in response to AS203 treatment signals activation of Bax and phosphorylation of Bcl-2, resulting in mitochondrial apoptotic cell death in human cervical cancer cells.