Chen Ku-Chung, Liu Wen-Hsin, Kao Pei-Hsiu, Chang Long-Sen
Institute of Biomedical Sciences, National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center, National Sun Yat-Sen University, Kaohsiung, Taiwan.
J Cell Physiol. 2010 Jan;222(1):177-86. doi: 10.1002/jcp.21934.
Notechis scutatus scutatus notexin induced apoptotic death of SK-N-SH cells accompanied with downregulation of Bcl-xL, upregulation of Bak, mitochondrial depolarization, and ROS generation. Upon exposure to notexin, Ca(2+)-mediated JNK and p38 MAPK activation were observed in SK-N-SH cells. Production of ROS was a downstream event followed by Ca(2+)-mediated mitochondrial alteration. Notexin-induced cell death, mitochondrial depolarization, and ROS generation were suppressed by SB202190 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor). Moreover, phospho-p38 MAPK and phospho-JNK were proved to be involved in Bcl-xL degradation, and overexpression of Bcl-xL attenuated the cytotoxic effect of notexin. Bak upregulation was elicited by p38 MAPK-mediated ATF-2 activation and JNK-mediated c-Jun activation. Suppression of Bak upregulation by ATF-2 siRNA or c-Jun siRNA attenuated notexin-evoked mitochondrial depolarization and rescued viability of notexin-treated cells. Taken together, our data indicate that notexin-induced apoptotic death of SK-N-SH cells is mediated through mitochondrial alteration triggering by Ca(2+)-evoked p38 MAPK/ATF-2 and JNK/c-Jun signaling pathways.
东部拟眼镜蛇毒液神经毒素可诱导SK-N-SH细胞发生凋亡性死亡，同时伴有Bcl-xL表达下调、Bak表达上调、线粒体去极化以及活性氧生成。在SK-N-SH细胞中，暴露于东部拟眼镜蛇毒液神经毒素后，可观察到Ca(2+)介导的JNK和p38丝裂原活化蛋白激酶（MAPK）激活。活性氧的产生是Ca(2+)介导的线粒体改变后的下游事件。SB202190（p38 MAPK抑制剂）和SP600125（JNK抑制剂）可抑制东部拟眼镜蛇毒液神经毒素诱导的细胞死亡、线粒体去极化和活性氧生成。此外，磷酸化p38 MAPK和磷酸化JNK被证明参与了Bcl-xL的降解，并且Bcl-xL的过表达减弱了东部拟眼镜蛇毒液神经毒素的细胞毒性作用。Bak表达上调是由p38 MAPK介导的ATF-2激活和JNK介导的c-Jun激活引起的。用ATF-2小干扰RNA（siRNA）或c-Jun siRNA抑制Bak表达上调可减弱东部拟眼镜蛇毒液神经毒素诱发的线粒体去极化，并挽救经东部拟眼镜蛇毒液神经毒素处理的细胞的活力。综上所述，我们的数据表明，东部拟眼镜蛇毒液神经毒素诱导的SK-N-SH细胞凋亡性死亡是通过Ca(2+)诱发的p38 MAPK/ATF-2和JNK/c-Jun信号通路触发线粒体改变来介导的。
