TY - JOUR
T1 - Triclabendazole Induces Pyroptosis by Activating Caspase-3 to Cleave GSDME in Breast Cancer Cells
AU - Yan, Liang
AU - Liu, Yi
AU - Ma, Xue-Feng
AU - Hou, Dan
AU - Zhang, Yu-Hui
AU - Sun, Yong
AU - Shi, Shan-Shan
AU - Forouzanfar, Tim
AU - Lin, Hai-Yan
AU - Fan, Jun
AU - Wu, Gang
N1 - Funding Information:
This work was supported by the National Nature Science Foundation of China (grant No. 81671029), the National Major Science and Technology Project of China (grant No. 2016YFC1102900), the Guangzhou Science, Technology and Innovation Commission (grant Nos. 201803040008 and 201704030024), the International Team for Implantology (grant Nos. 8812012 and 8682012), the Bureau of Education of Guangzhou Municipality (grant No. 1201610458), the Natural Science Foundation of Zhejiang Province (grant Nos. LQ18H140003 and LQY17H140023), the Science Technology Department of Zhejiang Province (grant No. 2017C33168), the Zhejiang Provincial Basic Public Welfare Research Project (grant No. GJ19H140001), and China’s National Key R&D Programs (NKPs, grant No. 2018YFB0407204). National Natural Science Foundation of China (81974430) and the Natural Science Foundation of Guangdong Province (2019A1515012037).
Publisher Copyright:
© Copyright © 2021 Yan, Liu, Ma, Hou, Zhang, Sun, Shi, Forouzanfar, Lin, Fan and Wu.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7/8
Y1 - 2021/7/8
N2 - Pyroptosis is a form of programmed cell death, in which gasdermin E (GSDME) plays an important role in cancer cells, which can be induced by activated caspase-3 on apoptotic stimulation. Triclabendazole is a new type of imidazole in fluke resistance and has been approved by the FDA for the treatment of fascioliasis and its functions partially acting through apoptosis-related mechanisms. However, it remains unclear whether triclabendazole has obvious anti-cancer effects on breast cancer cells. In this study, to test the function of triclabendazole on breast cancer, we treated breast cancer cells with triclabendazole and found that triclabendazole induced lytic cell death in MCF-7 and MDA-MB-231, and the dying cells became swollen with evident large bubbles, a typical sign of pyroptosis. Triclabendazole activates apoptosis by regulating the apoptoic protein levels including Bax, Bcl-2, and enhanced cleavage of caspase-8/9/3/7 and PARP. In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/pyroptosis is further induced by active caspase-3. Consistent with this, triclabendazole-induced GSDME–N-terminal fragment cleavage and pyroptosis were reduced by caspase-3–specific inhibitor (Ac-DEVD-CHO) treatment. Moreover, triclabendazole induced reactive oxygen species (ROS) elevation and increased JNK phosphorylation and lytic cell death, which could be rescued by the ROS scavenger (NAC), suggesting that triclabendazole-induced GSDME-dependent pyroptosis is related to the ROS/JNK/Bax-mitochondrial apoptotic pathway. Besides, we showed that triclabendazole significantly reduced the tumor volume by promoting the cleavage of caspase-3, PARP, and GSDME in the xenograft model. Altogether, our results revealed that triclabendazole induces GSDME-dependent pyroptosis by caspase-3 activation at least partly through augmenting the ROS/JNK/Bax-mitochondrial apoptotic pathway, providing insights into this on-the-market drug in its potential new application in cancer treatment.
AB - Pyroptosis is a form of programmed cell death, in which gasdermin E (GSDME) plays an important role in cancer cells, which can be induced by activated caspase-3 on apoptotic stimulation. Triclabendazole is a new type of imidazole in fluke resistance and has been approved by the FDA for the treatment of fascioliasis and its functions partially acting through apoptosis-related mechanisms. However, it remains unclear whether triclabendazole has obvious anti-cancer effects on breast cancer cells. In this study, to test the function of triclabendazole on breast cancer, we treated breast cancer cells with triclabendazole and found that triclabendazole induced lytic cell death in MCF-7 and MDA-MB-231, and the dying cells became swollen with evident large bubbles, a typical sign of pyroptosis. Triclabendazole activates apoptosis by regulating the apoptoic protein levels including Bax, Bcl-2, and enhanced cleavage of caspase-8/9/3/7 and PARP. In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/pyroptosis is further induced by active caspase-3. Consistent with this, triclabendazole-induced GSDME–N-terminal fragment cleavage and pyroptosis were reduced by caspase-3–specific inhibitor (Ac-DEVD-CHO) treatment. Moreover, triclabendazole induced reactive oxygen species (ROS) elevation and increased JNK phosphorylation and lytic cell death, which could be rescued by the ROS scavenger (NAC), suggesting that triclabendazole-induced GSDME-dependent pyroptosis is related to the ROS/JNK/Bax-mitochondrial apoptotic pathway. Besides, we showed that triclabendazole significantly reduced the tumor volume by promoting the cleavage of caspase-3, PARP, and GSDME in the xenograft model. Altogether, our results revealed that triclabendazole induces GSDME-dependent pyroptosis by caspase-3 activation at least partly through augmenting the ROS/JNK/Bax-mitochondrial apoptotic pathway, providing insights into this on-the-market drug in its potential new application in cancer treatment.
KW - breast cancer
KW - caspase-3
KW - gasdermin E
KW - pyroptosis
KW - triclabendazole
UR - http://www.scopus.com/inward/record.url?scp=85111014901&partnerID=8YFLogxK
U2 - 10.3389/fphar.2021.670081
DO - 10.3389/fphar.2021.670081
M3 - Article
C2 - 34305590
VL - 12
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
SN - 1663-9812
M1 - 670081
ER -