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Cr (VI) induces crosstalk between apoptosis and autophagy through endoplasmic reticulum stress in A549 cells
Chemico-Biological Interactions ( IF 4.7 ) Pub Date : 2018-10-25 , DOI: 10.1016/j.cbi.2018.10.024
Hong Ge , Zhiguo Li , Liping Jiang , Qiujuan Li , Chengyan Geng , Xiaofeng Yao , Xiaoxia Shi , Yong Liu , Jun Cao

Hexavalent chromium [Cr (VI)], which is widely found in occupational environments, is a recognized human carcinogen. In this study, the role of endoplasmic reticulum (ER) stress in Cr (VI)-induced crosstalk of apoptosis and autophagy was investigated. Cr (VI) resulted in ER stress by upregulating the expression of GRP78 and p-PERK. 4-Phenylbutyric acid (4PBA), an inhibitor of ER stress, reduced both Cr (VI)-induced apoptosis and autophagy, suggesting that ER stress played an important role in Cr (VI)-induced apoptosis and autophagy in A549 cells. Furthermore, Cr (VI)-induced apoptosis preceded autophagy. Z-VAD-FMK, the suppressor of apoptosis, repressed Cr (VI)-induced autophagy. Pretreatment with 3-MA, the inhibitor of autophagy, increased Cr (VI)-induced apoptosis. Exposure to Cr (VI) significantly reduced mitochondrial membrane potential (MMP) during Cr (VI) treatment for 6–12 h. However, Cr (VI)-reduced MMP rescued significantly after treatment with Cr (VI) for 24 h compared with that of 6 h and 12 h groups, suggesting that Cr (VI)-induced autophagy at 24 h might rescue Cr (VI)-induced decrease of MMP through engulfing damaged mitochondria and then inhibit apoptosis in A549 cells. Above all, our results indicated that Cr (VI)-induced ER stress plays an important role in the crosstalk between apoptosis and autophagy. The autophagy might be apoptosis-dependent and subsequently prevents apoptosis cell death to keep A549 cells resistant to Cr (VI)-induced further toxicity. This maybe underlies the mechanism of Cr (VI)-induced carcinogenesis.



中文翻译:

Cr(VI)通过内质网应激诱导A549细胞凋亡与自噬之间的串扰

在职业环境中广泛发现的六价铬[Cr(VI)]是公认的人类致癌物。在这项研究中,研究了内质网应激在六价铬诱导的细胞凋亡和自噬串扰中的作用。Cr(VI)通过上调GRP78和p-PERK的表达而导致内质网应激。ER应激抑制剂4-苯基丁酸(4PBA)减少了Cr(VI)诱导的凋亡和自噬,这表明ER应激在Cr(VI)诱导的A549细胞凋亡和自噬中起着重要作用。此外,Cr(VI)诱导的细胞凋亡先于自噬。Z-VAD-FMK,细胞凋亡的抑制因子,抑制了Cr(VI)诱导的自噬。自噬抑制剂3-MA的预处理增加了Cr(VI)诱导的细胞凋亡。Cr(VI)处理6-12 h期间,暴露于Cr(VI)会大大降低线粒体膜电位(MMP)。但是,Cr(VI)还原的MMP在Cr(VI)处理24 h后较6 h和12 h组明显恢复,这表明Cr(VI)在24 h诱导的自噬可能会恢复Cr(VI)。吞噬受损的线粒体,诱导MMP降低,然后抑制A549细胞的凋亡。最重要的是,我们的结果表明,Cr(VI)诱导的内质网应激在细胞凋亡与自噬之间的串扰中起着重要作用。自噬可能是凋亡依赖性的,并随后阻止凋亡细胞死亡,以保持A549细胞对Cr(VI)诱导的进一步毒性具有抗性。这可能是六价铬(Cr)诱导癌变的机制的基础。Cr(VI)减少24小时后,Cr(VI)还原的MMP得以显着恢复,而6 h和12 h组明显降低,这表明Cr(VI)诱导的24 h自噬可能会挽救Cr(VI)诱导的通过吞噬受损的线粒体降低MMP,然后抑制A549细胞凋亡。最重要的是,我们的结果表明,Cr(VI)诱导的内质网应激在细胞凋亡与自噬之间的串扰中起着重要作用。自噬可能是凋亡依赖性的,并随后阻止凋亡细胞死亡,以保持A549细胞对Cr(VI)诱导的进一步毒性具有抗性。这可能是六价铬(Cr)诱导癌变的机制的基础。Cr(VI)减少24小时后,Cr(VI)还原的MMP得以显着恢复,而6 h和12 h组明显降低,这表明Cr(VI)诱导的24 h自噬可能会挽救Cr(VI)诱导的通过吞噬受损的线粒体降低MMP,然后抑制A549细胞凋亡。最重要的是,我们的结果表明,Cr(VI)诱导的内质网应激在细胞凋亡与自噬之间的串扰中起着重要作用。自噬可能是凋亡依赖性的,并随后阻止凋亡细胞死亡,以保持A549细胞对Cr(VI)诱导的进一步毒性具有抗性。这可能是六价铬(Cr)诱导癌变的机制的基础。提示Cr(VI)诱导的24小时自噬可能通过吞噬受损的线粒体来挽救Cr(VI)诱导的MMP降低,然后抑制A549细胞的凋亡。最重要的是,我们的结果表明,Cr(VI)诱导的内质网应激在细胞凋亡与自噬之间的串扰中起着重要作用。自噬可能是凋亡依赖性的,并随后阻止凋亡细胞死亡,以保持A549细胞对Cr(VI)诱导的进一步毒性具有抗性。这可能是六价铬(Cr)诱导癌变的机制的基础。提示Cr(VI)诱导的24小时自噬可能通过吞噬受损的线粒体来挽救Cr(VI)诱导的MMP降低,然后抑制A549细胞的凋亡。最重要的是,我们的结果表明,Cr(VI)诱导的内质网应激在细胞凋亡与自噬之间的串扰中起着重要作用。自噬可能是凋亡依赖性的,并随后阻止凋亡细胞死亡,以保持A549细胞对Cr(VI)诱导的进一步毒性具有抗性。这可能是六价铬(Cr)诱导癌变的机制的基础。自噬可能是凋亡依赖性的,并随后阻止凋亡细胞死亡,以保持A549细胞对Cr(VI)诱导的进一步毒性具有抗性。这可能是六价铬(Cr)诱导癌变的机制的基础。自噬可能是凋亡依赖性的,并随后阻止凋亡细胞死亡,以保持A549细胞对Cr(VI)诱导的进一步毒性具有抗性。这可能是六价铬(Cr)诱导癌变的机制的基础。

更新日期:2018-10-25
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