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Apoptosis

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Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation

  • Cheng-cheng Zhang
  • Chen-guang Li
  • Yao-feng Wang
  • Li-hui Xu
  • Xian-hui He
  • Qiong-zhen Zeng
  • Chen-ying Zeng
  • Feng-yi Mai
  • Bo HuEmail author
  • Dong-yun OuyangEmail author
Article
  • 71 Downloads

Abstract

Gasdermin E (GSDME) has an important role in inducing secondary necrosis/pyroptosis. Upon apoptotic stimulation, it can be cleaved by activated caspase-3 to generate its N-terminal fragment (GSDME-NT), which executes pyroptosis by perforating the plasma membrane. GSDME is expressed in many human lung cancers including A549 cells. Paclitaxel and cisplatin are two representative chemotherapeutic agents for lung cancers, which induce apoptosis via different action mechanisms. However, it remains unclear whether they can induce GSDME-mediated secondary necrosis/pyroptosis in lung A549 cancer cells. Here we showed that both paclitaxel and cisplatin evidently induced apoptosis in A549 cells as revealed by the activation of multiple apoptotic markers. Notably, some of the dying cells displayed characteristic morphology of secondary necrosis/pyroptosis, by blowing large bubbles from the cellular membrane accompanied by caspase-3 activation and GSDME-NT generation. But the ability of cisplatin to induce this phenomenon was much stronger than that of paclitaxel. Consistent with this, cisplatin triggered much higher activation of caspase-3 and generation of GSDME-NT than paclitaxel, suggesting that the levels of secondary necrosis/pyroptosis correlated with the levels of active caspase-3 and GSDME-NT. Supporting this, caspase-3 specific inhibitor (Ac-DEVD-CHO) suppressed cisplatin-induced GSDME-NT generation and concurrently reduced the secondary necrosis/pyroptosis. Besides, GSDME knockdown significantly inhibited cisplatin- but not paclitaxel-induced secondary necrosis/pyroptosis. These results indicated that cisplatin induced higher levels of secondary necrosis/pyroptosis in A549 cells than paclitaxel, suggesting that cisplatin may provide additional advantages in the treatment of lung cancers with high levels of GSDME expression.

Keywords

Pyroptosis Secondary necrosis Cisplatin Paclitaxel GSDME Caspase-3 

Notes

Acknowledgements

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 81873064, 81773965 and 81673664).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

10495_2019_1515_MOESM1_ESM.pdf (2.1 mb)
Supplementary material 1 (PDF 2176 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Immunobiology, College of Life Science and TechnologyJinan UniversityGuangzhouChina
  2. 2.Department of Cell Biology, College of Life Science and TechnologyJinan UniversityGuangzhouChina
  3. 3.Department of NephrologyThe First Affiliated Hospital of Jinan UniversityGuangzhouChina

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