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Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-02-25 , DOI: 10.1038/s41419-019-1441-4 Junhui Yu 1 , Shan Li 2 , Jie Qi 3 , Zilu Chen 1 , Yunhua Wu 1 , Jing Guo 1 , Kai Wang 1 , Xuejun Sun 1 , Jianbao Zheng 1
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-02-25 , DOI: 10.1038/s41419-019-1441-4 Junhui Yu 1 , Shan Li 2 , Jie Qi 3 , Zilu Chen 1 , Yunhua Wu 1 , Jing Guo 1 , Kai Wang 1 , Xuejun Sun 1 , Jianbao Zheng 1
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Pyroptosis, a form of programmed cell death (PCD), has garnered increasing attention as it relates to innate immunity and diseases. However, the involvement of pyroptosis in the mechanism by which lobaplatin acts against colorectal cancer (CRC) is unclear. Our study revealed that treatment with lobaplatin reduced the viability of HT-29 and HCT116 cells in a dose-dependent manner. Morphologically, HT-29 and HCT116 cells treated with lobaplatin exhibited microscopic features of cell swelling and large bubbles emerging from the plasma membrane, and transmission electron microscopy (TEM) revealed multiple pores in the membrane. GSDME, rather than GSDMD, was cleaved in lobaplatin-induced pyroptosis in HT-29 and HCT116 cells due to caspase-3 activation. Knocking out GSDME switched lobaplatin-induced cell death from pyroptosis to apoptosis but did not affect lobaplatin-mediated inhibition of growth and tumour formation of HT-29 and HCT116 cells in vivo and in vitro. Further investigation indicates that lobaplatin induced reactive oxygen species (ROS) elevation and JNK phosphorylation. NAC, a ROS scavenger, completely reversed the pyroptosis of lobaplatin-treated HT-29 and HCT116 and JNK phosphorylation. Activated JNK recruited Bax to mitochondria, and thereby stimulated cytochrome c release to cytosol, followed by caspase-3/-9 cleavage and pyroptosis induction. Therefore, in colon cancer cells, GSDME mediates lobaplatin-induced pyroptosis downstream of the ROS/JNK/Bax-mitochondrial apoptotic pathway and caspase-3/-9 activation. Our study indicated that GSDME-dependent pyroptosis is an unrecognized mechanism by which lobaplatin eradicates neoplastic cells, which may have important implications for the clinical application of anticancer therapeutics.
中文翻译：
caspase-3对GSDME的切割决定了洛巴铂诱导的结肠癌细胞的凋亡。
程序性细胞死亡（PCD）是一种程序性细胞死亡，由于它与先天免疫和疾病有关，因此引起了越来越多的关注。但是，尚不清楚焦磷酸是否参与洛巴铂抗结直肠癌（CRC）的机制。我们的研究表明，洛巴铂治疗以剂量依赖性方式降低了HT-29和HCT116细胞的活力。形态上，用洛铂处理的HT-29和HCT116细胞表现出细胞肿胀的微观特征和从质膜上出现的大气泡，而透射电子显微镜（TEM）则显示了膜中的多个孔。由于caspase-3激活，GSDME（而不是GSDMD）在洛巴铂诱导的HT-29和HCT116细胞凋亡中被裂解。敲除GSDME可将洛铂铂诱导的细胞死亡从焦磷酸转变为凋亡，但在体内外均不影响洛铂介导的HT-29和HCT116细胞的生长以及肿瘤形成的抑制作用。进一步的研究表明，洛铂会引起活性氧（ROS）升高和JNK磷酸化。NAC是一种ROS清除剂，它完全逆转了洛巴铂处理的HT-29和HCT116的焦磷酸化作用以及JNK的磷酸化作用。活化的JNK将Bax募集到线粒体，从而刺激细胞色素c释放到细胞质中，然后进行caspase-3 / -9裂解和光解。因此，在结肠癌细胞中，GSDME在ROS / JNK / Bax线粒体凋亡途径和caspase-3 / -9激活的下游介导了洛巴铂诱导的凋亡。
更新日期：2019-02-25
中文翻译：
caspase-3对GSDME的切割决定了洛巴铂诱导的结肠癌细胞的凋亡。
程序性细胞死亡（PCD）是一种程序性细胞死亡，由于它与先天免疫和疾病有关，因此引起了越来越多的关注。但是，尚不清楚焦磷酸是否参与洛巴铂抗结直肠癌（CRC）的机制。我们的研究表明，洛巴铂治疗以剂量依赖性方式降低了HT-29和HCT116细胞的活力。形态上，用洛铂处理的HT-29和HCT116细胞表现出细胞肿胀的微观特征和从质膜上出现的大气泡，而透射电子显微镜（TEM）则显示了膜中的多个孔。由于caspase-3激活，GSDME（而不是GSDMD）在洛巴铂诱导的HT-29和HCT116细胞凋亡中被裂解。敲除GSDME可将洛铂铂诱导的细胞死亡从焦磷酸转变为凋亡，但在体内外均不影响洛铂介导的HT-29和HCT116细胞的生长以及肿瘤形成的抑制作用。进一步的研究表明，洛铂会引起活性氧（ROS）升高和JNK磷酸化。NAC是一种ROS清除剂，它完全逆转了洛巴铂处理的HT-29和HCT116的焦磷酸化作用以及JNK的磷酸化作用。活化的JNK将Bax募集到线粒体，从而刺激细胞色素c释放到细胞质中，然后进行caspase-3 / -9裂解和光解。因此，在结肠癌细胞中，GSDME在ROS / JNK / Bax线粒体凋亡途径和caspase-3 / -9激活的下游介导了洛巴铂诱导的凋亡。
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