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Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells

Open access
Yu, Junhui, Li, Shan, Qi, Jie, Chen, Zilu, Wu, Yunhua, Guo, Jing, Wang, Kai, Sun, Xuejun, Zheng, Jianbao·2019·Cell Death & Disease

Abstract

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.

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Metadata

Authors
Yu, J., Li, S., Qi, J., Chen, Z., Wu, Y., Guo, J., Wang, K., Sun, X., & Zheng, J.
Venue
Cell Death & Disease
Published
2019-02-25
Volume
10
Issue
3
Pages
193-193
ISSN
2041-4889 (ISSN-L)
OpenAlex
W2917633868
Cited by
483
References
12
FWCI
16.18
Type
journal article
Language
en
Open access
gold

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CoChat. (2026). Citation check: Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells. https://app.cochat.ai/papers/10.1038/s41419-019-1441-4
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Yu, J., Li, S., Qi, J., Chen, Z., Wu, Y., Guo, J., Wang, K., Sun, X., & Zheng, J. (2019). Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells. Cell Death & Disease. https://doi.org/10.1038/s41419-019-1441-4

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