Celastrol activates caspase-3/GSDME-dependent pyroptosis in tumor cells by inducing endoplasmic reticulum stress Author links open overlay panel  

作　　者：Jiajian Guo Dongxiao Cui Yuping Tang Sanjiao Wang Cuiyan Ma Wenfu Ma 

机构地区：[1]School of Life Sciences,Beijing University of Chinese Medicine,Beijing 102488,China [2]Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility,Shaanxi University of Chinese Medicine,Xi'an 712046,China [3]School of Literature and History,Mianyang Teachers'College,Mianyang 621000,China

出　　处：《Journal of Traditional Chinese Medical Sciences》2024年第3期330-339,共10页中医科学杂志（英文）

基　　金：supported by grants from startup fund program at Beijing University of Chinese Medicine(90011451310011);key research fund for drug discovery in Chinese medicine at Beijing University of Chinese Medicine(1000061223476);startup fund program at Beijing University of Chinese Medicine(90020361220006).

摘　　要：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.

关 键 词：CELASTROL Tumor cells PYROPTOSIS GSDME CASPASE-3 Endoplasmic reticulum stress stress Cell death Traditional Chinese medicine 

分 类 号：R285[医药卫生—中药学]