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Caspase-3-mediated GSDME induced Pyroptosis in breast cancer cells through the ROS/JNK signalling pathway.

ABSTRACT: Pyroptosis is a new form of programmed cell death generated by some inflammasomes, piloting the cleavage of gasdermin (GSDM) and stimulation of dormant cytokines like IL-18 and IL-1β; these reactions are narrowly linked to certain diseases like diabetic nephropathy and atherosclerosis. Doxorubicin, a typical anthracycline, and famous anticancer drug has emerged as a prominent medication in several cancer chemotherapies, although its application is accompanied with expending of dose-dependent, increasing, irreversible and continuing cardiotoxic side effects. However, the exact path that links the induced pyroptosis to the mechanism by which Doxorubicin (DOX) acts against breast cancer cells is still puzzling. The present study seeks to elucidate the potential link between DOX-induced cell death and pyroptosis in two human breast cancer cell lines (MDA-MB-231 and T47D). We proved that treatment with DOX reduced the cell viability in a dose-dependent way and induced pyroptosis morphology in MDA-MB-231 and T47D cells. Also, protein expression analyses revealed GSDME as a key regulator in DOX-induced pyroptosis and highlighted the related role of Caspase-3 activation. Furthermore, DOX treatments induced intracellular accumulation of ROS, stimulated the phosphorylation of JNK, and Caspase-3 activation, subsequently. In conclusion, the study suggests that GSDME triggered DOX-induced pyroptosis in the caspase-3 dependent reactions through the ROS/JNK signalling pathway. Additionally, it showed that the DOX-induced cardiotoxicity and pyroptosis in breast cancer cells can be minimized by reducing the protein level of GSDME; thus, these outcomes provide a new research target and implications for the anticancer investigations and therapeutic applications.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC8419174 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:Pyroptosis is a recently identified type of lytic programmed cell death, in which pores form in the plasma membrane, and cells swell, rupture, and then release their contents, including inflammatory cytokines. Molecular studies indicated that pyroptosis may occur via a gasdermin D (GSDMD) and caspase-1 (Casp1) -dependent classical pathway, a GSDMD and Casp11/4/5-dependent non-classical pathway, or a gasdermin E (GSDME) and Casp3-dependent pathway. Studies of animal models and humans indicated that pyroptosis can exacerbate several complications of diabetes, including diabetic nephropathy (DN), a serious microvascular complication of diabetes. Many studies investigated the mechanism mediating the renoprotective effect of GSDMD regulation in the kidneys of patients and animal models with diabetes. As a newly discovered regulatory mechanism, GSDME and Casp3-dependent pyroptotic pathway in the progression of DN has also attracted people's attention. Z-DEVD-FMK, an inhibitor of Casp3, ameliorates albuminuria, improves renal function, and reduces tubulointerstitial fibrosis in diabetic mice, and these effects are associated with the inhibition of GSDME. Studies of HK-2 cells indicated that the molecular and histological features of secondary necrosis were present following glucose stimulation due to GSDME cleavage, such as cell swelling, and release of cellular contents. Therefore, therapies targeting Casp3/GSDME-dependent pyroptosis have potential for treatment of DN. A novel nephroprotective strategy that employs GSDME-derived peptides which are directed against Casp3-induced cell death may be a key breakthrough. This mini-review describes the discovery and history of research in this pyroptosis pathway and reviews the function of proteins in the gasdermin family, with a focus on the role of GSDME-mediated pyroptosis in DN. Many studies have investigated the impact of GSDME-mediated pyroptosis in kidney diseases, and these studies used multiple interventions, in vitro models, and in vivo models. We expect that further research on the function of GDSME in DN may provide valuable insights that may help to improve treatments for this disease.

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Caspase-3-mediated GSDME induced Pyroptosis in breast cancer cells through the ROS/JNK signalling pathway.

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