Celastrol activates caspase-3/GSDME-dependent pyroptosis in tumor cells by inducing endoplasmic reticulum stress
- Author:
Jiajian Guo
;
Dongxiao Cui
;
Yuping Tang
;
Sanjiao Wang
;
Cuiyan Ma
;
Wenfu Ma
1
Author Information
1. wenfuma@bucm.edu.cn
- Publication Type:期刊文章
- Keywords:
Celastrol;
Tumor cells;
Pyroptosis;
GSDME;
Caspase-3;
Endoplasmic reticulum stress stress;
Cell death;
Traditional Chinese medicine
- From:
Journal of Traditional Chinese Medical Sciences
2024;11(3):330-339
- CountryChina
- Language:English
-
Abstract:
Objective:To investigate the pyroptosis-inducing effects of celastrol on tumor cells and to explore the potential mechanisms involved, specifically focusing on the role of the caspase-3/gasdermin E (GSDME) signaling pathway and the impact of endoplasmic reticulum (ER) stress and autophagy.
Methods:Necrostatin-1 (Nec-1), lactate dehydrogenase release (LDH) assay, and Hoechst/propidium iodide (PI) double staining were employed to validate the mode of cell death. Western blot was used to detect the cleavage of GSDME and the expression of light chain 3 (LC3) and BIP.
Results:Celastrol induced cell swelling with large bubbles, which is consistent with the pyroptotic phenotype. Moreover, treatment with celastrol induced GSDME cleavage, indicating the activation of GSDME-mediated pyroptosis. GSDME knockout via CRISPR/Cas9 blocked the pyroptotic morphology of celastrol in HeLa cells. In addition, cleavage of GSDME was attenuated by a specific caspase-3 inhibitor in celastrol-treated cells, suggesting that GSDME activation was induced by caspase-3. Mechanistically, celastrol induced endoplasmic reticulum (ER) stress and autophagy in HeLa cells, and other ER stress inducers produced effects consistent with those of celastrol.
Conclusion:These findings suggest that celastrol triggers caspase-3/GSDME-dependent pyroptosis via activation of ER stress, which may shed light on the potential antitumor clinical applications of celastrol.
