The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

Jiang, Mingxia; Qi, Ling; Li, Lisha; Li, Yanjing

doi:10.1038/s41420-020-00349-0

Cited by 395 publications

(309 citation statements)

References 73 publications

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“…Caspase-3 is the most important terminal cleavage enzyme in the process of apoptosis and cleaved-caspase-3 is the activated form of caspase-3 (27). Through western blotting changes in the expression of the apoptosis-related protein cleaved caspase-3 were found in the present study.…”

Section: Discussionsupporting

confidence: 49%

Apoptosis in HUVECs induced by microRNA‑616‑3p via X‑linked inhibitor of apoptosis protein targeting

Chen

Liu

et al. 2021

Exp Ther Med

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Atherosclerosis causes stroke and coronary heart disease and is associated with a high mortality rate worldwide. However, the pathogenesis of atherosclerosis remains unclear. Endothelial cell apoptosis is one of the early changes observed in atherosclerosis. Previous studies have found that microRNA (miR)-616-3p may be involved in the development of atherosclerosis, but the specific mechanism is not clear. The present study aimed to investigate whether miR-616-3p is involved in endothelial cell apoptosis and its underlying mechanism. The present study demonstrated that compared with normal HUVECs, HUVECs treated with oxidized low-density lipoprotein expressed higher miR-616-3p and lower X-linked inhibitor of apoptosis protein (XIAP) levels. In the present study, HUVECs were transfected with miR-616-3p mimic and Cell Counting Kit-8 (CCK-8), flow cytometry and TUNEL staining assays demonstrated that compared with miR-616-3p mimic control, the miR-616-3p mimic promoted HUVEC apoptosis. In addition, using StarBase 3.0 for bioinformatics analysis it was predicted that miR-616-3p may bind to the 3'untranslated region (UTR) of XIAP mRNA. The present study performed the CCK-8, flow cytometry, TUNEL staining and dual-luciferase reporter assays and demonstrated that miR-616-3p binds to the 3'UTR of the XIAP mRNA and inhibits its expression and that this further promotes apoptosis in HUVECs. In addition, western blotting demonstrated that compared with miR-616-3p mimic control, the miR-616-3p mimic increases the level of cleaved caspase-3 in HUVECs. In summary, the present study demonstrated that miR-616-3p can directly inhibit the expression of XIAP mRNA by targeting its 3'UTR which promoted apoptosis in HUVECs. miR-616-3p and XIAP may be used as therapeutic targets of atherosclerosis in the future.

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Section: Discussionsupporting

confidence: 49%

Apoptosis in HUVECs induced by microRNA‑616‑3p via X‑linked inhibitor of apoptosis protein targeting

Chen

Liu

et al. 2021

Exp Ther Med

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“…Our data showed that GSDME is the major executor responsible for TPL induced pyroptosis in head and neck cancer cells. Until recently, it has been recognized that gasdermins pore forming proteins, not caspases, are determinant of cell death type [ 42 ]. In GSDME-expressing cells, active caspase 3 cleaves GSDME and liberates the pore-forming ability of N-terminus, resulting in cell swelling, membrane rupture, and pyroptotic cell death.…”

Section: Discussionmentioning

confidence: 99%

Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ

Cai

Man

Tan

et al. 2021

J Exp Clin Cancer Res

129

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Background Pyroptosis is a lytic cell death form executed by gasdermins family proteins. Induction of tumor pyroptosis promotes anti-tumor immunity and is a potential cancer treatment strategy. Triptolide (TPL) is a natural product isolated from the traditional Chinese herb which possesses potent anti-tumor activity in human cancers. However, its role in pyroptosis remains to be elucidated. Methods Cell survival was measured by colony formation assay. Cell apoptosis was determined by Annexin V assay. Pyroptosis was evaluated by morphological features and release of interleukin 1β and lactate dehydrogenase A (LDHA). Immunofluorescence staining was employed to measure subcellular localization of proteins. Tumorigenicity was assessed by a xenograft tumor model. Expression levels of mRNAs or proteins were determined by qPCR or western blot assay, respectively. Results Triptolide eliminates head and neck cancer cells through inducing gasdermin E (GSDME) mediated pyroptosis. Silencing GSDME attenuates the cytotoxicity of TPL against cancer cells. TPL treatment suppresses expression of c-myc and mitochondrial hexokinase II (HK-II) in cancer cells, leading to activation of the BAD/BAX-caspase 3 cascade and cleavage of GSDME by active caspase 3. Silencing HK-II sensitizes cancer cells to TPL induced pyroptosis, whereas enforced expression of HK-II prevents TPL induced pyroptosis. Mechanistically, HK-II prevents mitochondrial translocation of BAD, BAX proteins and activation of caspase 3, thus attenuating cleavage of GSDME and pyroptosis upon TPL treatment. Furthermore, TPL treatment suppresses NRF2/SLC7A11 (also known as xCT) axis and induces reactive oxygen species (ROS) accumulation, regardless of the status of GSDME. Combination of TPL with erastin, an inhibitor of SLC7A11, exerts robust synergistic effect in suppression of tumor survival in vitro and in a nude mice model. Conclusions This study not only provides a new paradigm of TPL in cancer therapy, but also highlights a crucial role of mitochondrial HK-II in linking glucose metabolism with pyroptosis.

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“…Further studies may focus on whether/how PJVK participates in pyroptosis and tumour suppression. CASP3 exists as a non-activated zymogen in its normal state, but upon activation, it produces active executors that cleave structural and regulatory proteins in the nucleus and cytoplasm of cells, thereby regulating cell death, and it is recognized as a marker of apoptosis 30 . In 2017, Wang et al 31 discovered that GSDME was specifically cleaved by chemotherapeutic drug-activated CASP3 to produce a membrane-penetrating GSDME -N fragment, which induced pyroptosis.…”

Section: Discussionmentioning

confidence: 99%

A novel defined pyroptosis-related gene signature for predicting the prognosis of ovarian cancer

2021

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Ovarian cancer (OC) is a highly malignant gynaecological tumour that has a very poor prognosis. Pyroptosis has been demonstrated in recent years to be an inflammatory form of programmed cell death. However, the expression of pyroptosis-related genes in OC and their correlations with prognosis remain unclear. In this study, we identified 31 pyroptosis regulators that were differentially expressed between OC and normal ovarian tissues. Based on these differentially expressed genes (DEGs), all OC cases could be divided into two subtypes. The prognostic value of each pyroptosis-related gene for survival was evaluated to construct a multigene signature using The Cancer Genome Atlas (TCGA) cohort. By applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, a 7-gene signature was built and classified all OC patients in the TCGA cohort into a low- or high-risk group. OC patients in the low-risk group showed significantly higher survival possibilities than those in the high-risk group (P < 0.001). Utilizing the median risk score from the TCGA cohort, OC patients from a Gene Expression Omnibus (GEO) cohort were divided into two risk subgroups, and the low-risk group had increased overall survival (OS) time (P = 0.014). Combined with the clinical characteristics, the risk score was found to be an independent factor for predicting the OS of OC patients. Gene ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) analyses indicated that immune-related genes were enriched and that the immune status was decreased in the high-risk group. In conclusion, pyroptosis-related genes play important roles in tumour immunity and can be used to predict the prognosis of OCs.

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The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

Cited by 395 publications

References 73 publications

Apoptosis in HUVECs induced by microRNA‑616‑3p via X‑linked inhibitor of apoptosis protein targeting

Apoptosis in HUVECs induced by microRNA‑616‑3p via X‑linked inhibitor of apoptosis protein targeting

Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ

A novel defined pyroptosis-related gene signature for predicting the prognosis of ovarian cancer

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