ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction underlie apoptosis induced by resveratrol and arsenic trioxide in A549 cells
ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction underlie apoptosis induced by resveratrol and arsenic trioxide in A549 cells
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ROS介导的内质网应激和线粒体功能障碍是白藜芦醇和三氧化二砷诱导A549细胞凋亡的基础
DOI：
10.1016/j.cbi.2016.01.005
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发表时间：
2016-02-05
影响因子：
5.1
通讯作者：
Zhang, Zunzhen
中科院分区：
文献类型：
--
作者：
Gu, Shiyan;Chen, Chengzhi;Zhang, Zunzhen
虽然内质网（ER）应激和线粒体功能障碍与细胞凋亡相关的研究已得到充分证实，但它们是否参与白藜芦醇和三氧化二砷（ATO）联合诱导的凋亡细胞死亡尚不清楚。在本研究中，我们发现白藜芦醇对人肺腺癌A549细胞对ATO的一系列增敏作用，且白藜芦醇与ATO的联合指数（CI）均小于1。然后，我们证明内质网应激促进了这种协同效应，这表现在内质网应激标志的表达水平增加，包括78- kda葡萄糖调节蛋白（grp78）、caspase 12和C/ ebp同源蛋白（CHOP）。此外，A549细胞暴露于白藜芦醇或/和ATO后观察到线粒体功能障碍，这表现在线粒体相关事件的一些改变，如线粒体膜电位的丧失。细胞色素c释放及Bax、Bcl-2表达变化。我们的研究结果进一步证明，白藜芦醇和ATO诱导的内质网应激和线粒体功能障碍是由活性氧（ROS）介导的，表明预处理n -乙酰- l-半胱氨酸（一种有效的ROS清除剂）可以恢复与白藜芦醇和ATO共处理的细胞的内质网应激和线粒体功能障碍，从而减少细胞凋亡。综上所述，这些结果清楚地表明，ros介导的内质网应激和线粒体功能障碍参与了白藜芦醇和ATO诱导的A549细胞凋亡，这为白藜芦醇介导ATO致敏的分子机制提供了新的见解。2016爱思唯尔爱尔兰有限公司版权所有。
Although it is well documented that endoplasmic reticulum (ER) stress and mitochondrial dysfunction are associated with apoptosis, little is known about whether they are involved in the apoptotic cell death induced by resveratrol and arsenic trioxide (ATO) combination. In this study, we identified a series of sensitization effects of resveratrol on human lung adenocarcinoma A549 cells to ATO treatment, with the combination index (CI) of resveratrol and ATO less than 1. Then, we demonstrated that ER stress was contributed to this synergistic effect, which was manifested by increased the expression levels of ER stress hallmarks, including 78-kDa glucose-regulated protein (GRP 78), caspase 12 and C/EBP-homologous protein (CHOP), In addition, mitochondrial dysfunction was observed after exposure of A549 cells to resveratrol or/and ATO, which was displayed by some alterations of mitochondria-related events, such as loss of mitochondrial membrane potential, cytochrome c release and changes of Bax and Bcl-2 expressions. Our results further demonstrated that resveratrol and ATO-induced ER stress and mitochondrial dysfunction were mediated by reactive oxygen species (ROS), showing that pre-treatment of N-acetyl-L-cysteine, a potent ROS scavenger, restored the ER stress and mitochondrial dysfunction in cells co-treated with resveratrol and ATO, thereby leading to the reduction of the apoptosis. Collectively, these results clearly suggest that ROS-mediated ER stress and mitochondrial dysfunction were involved in the apoptosis induced by resveratrol and ATO in A549 cells, which provides a novel insight into the molecular mechanisms of resveratrol-mediated ATO-sensitization. (C) 2016 Elsevier Ireland Ltd. All rights reserved.