Apoptin induces pyroptosis of colorectal cancer cells via the GSDME-dependent pathway

Liu, Zirui; Li, Yiquan; Zhu, Yan; Li, Nan; Li, Wenjie; Shang, Chao; Song, Gaojie; Li, Shanzhi; Cong, Jianan; Li, Tingyu; Xiu, Zhiru; Lü, Jing; Ge, Chenchen; Yang, Xia; Sun, Lili; Li, Xiao; Jin, Ningyi

doi:10.7150/ijbs.64350

Cited by 44 publications

(27 citation statements)

References 42 publications

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“…But, the cleaved GSDMD cannot be detected in osthole-induced HeLa cells (supplementary Figure S4 ). Among the alternative pathways, the most widely studied is GSDME-induced pyroptosis through caspase-3 [ 30 ]. GSDME is a member of the gasdermin family which contains a cytotoxic N-terminal domain to form pore and induce membrane permeabilization.…”

Section: Discussionmentioning

confidence: 99%

Osthole Induces Apoptosis and Caspase-3/GSDME-Dependent Pyroptosis via NQO1-Mediated ROS Generation in HeLa Cells

Wang

Huangfu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Osthole is a natural coumarin which has been proved to inhibit growth of cancer cells by inducing cell death, while its mechanism was considered to be just caused by apoptosis. In our study, we found that osthole activated not just apoptosis, but also pyroptosis which is a form of regulated cell death accompanied by loss of cell membrane integrity and lactate dehydrogenase (LDH) release. Caspase-3 is a key protein of apoptosis as well as pyroptosis. The apoptosis and pyroptosis induced by osthole were all inhibited by irreversible caspase-3 inhibitor Z-DEVD-FMK. Meanwhile, knockdown of gasdermin E (GSDME) only reduced the osthole-induced pyroptosis but did not affect the occurrence of apoptosis. Our proteomic analysis revealed that the expression of NAD(P)H: quinone oxidoreductase 1 (NQO1) was decreased in osthole-treated cells. Moreover, NQO1 inhibition by osthole induced the overproduction of reactive oxygen species (ROS), as well as apoptosis and pyroptosis. ROS inhibitor N-Acetyl-L-cysteine (NAC) not only reduced osthole-induced apoptosis but also reversed its effect on the pyroptosis. Meanwhile, knockdown of NQO1 by si-NQO1 or its inhibitor dicoumarol (DIC) not only enhanced ROS generation but also strengthened the GSDME-mediated pyroptosis. Finally, we demonstrated that osthole inhibited tumor growth and the expression of NQO1 in a HeLa xenograft mode. Similar to the results in vitro, osthole stimulated the activation of caspase-3, PARP, and GSDME in vivo. Taken together, all these data suggested that osthole induced apoptosis and caspase-3/GSDME-mediated pyroptosis via NQO1-mediated ROS accumulation.

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Section: Discussionmentioning

confidence: 99%

Osthole Induces Apoptosis and Caspase-3/GSDME-Dependent Pyroptosis via NQO1-Mediated ROS Generation in HeLa Cells

Wang

Huangfu

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…8). Although FB1 showed pro-apoptotic effects (Hou et al, 2021), the FB1 concentration used was of low-dose as demonstrated by the weight change and lung histopathology, however, low-dose FB1 only upregulated the pro-apoptosis protein Caspase 9 both in vivo and in vitro, recent researches have proved that Caspase 9 is also attributed to pyroptosis activation (Liu et al, 2022), as our results showed, low-dose FB1 induced signi cant in ammatory response and pyroptosis-related protein expressions in mouse lung and A549. Furthermore, our results showed that apoptosis didn't contribute to the FB1-promoted in ammatory response and injury (Fig.…”

Section: Discussionmentioning

confidence: 99%

Fumonisin B1 aggravates inflammatory injury via mTORC1/pyroptosis, while promotes viral replication via mTORC1/apoptosis in Canine influenza virus-infected mice and A549 cells

Liu

Zhang

et al. 2022

Preprint

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Canine influenza virus (CIV) has spread across the world and been a risk to canine and human. Fumonisin B1 (FB1) is a mycotoxin in feed and food, its pollution is low-level but very common. The co-occurrence of FB1 exposure and CIV infection is unavoidable. Here, we investigated the effects of low-dose FB1 exposure on CIV-induced inflammatory injury, viral replication and the underlying mechanisms in vivo and in vitro. In CIV-infected mice, low-dose FB1 (0.25, 0.5 and 0.75 mg/kg p.i.) treatment promoted systemic and lung inflammatory injury, as demonstrated by increased expressions of pro-inflammatory cytokines in serum and lung, increased occurrence of hemophagocytosis in spleen, promoted macrophage aggregation in lung, aggravated barrier damage and pathological injury of lung. In CIV-infected pulmonary epithelial model A549 cells, low-dose FB1 treatment significantly promoted the increase in pro-inflammatory cytokines expressions and the decrease in tight junction proteins expressions. Meanwhile, FB1 treatment promoted viral replication in mice and A549. Importantly, FB1 promoted CIV-inhibited mTOR/P70S6K signaling pathway and CIV-induced NLRP3-dependent pyroptosis, and inhibited CIV-induced apoptosis. Furthermore, mTORC1 inhibitor rapamycin blocked FB1-promoted pyroptosis, promoted FB1-inhibited apoptosis, and reversed FB1-promoted inflammatory injury and viral replication. NLRP3 inhibitor MCC950 attenuated FB1-aggravated inflammatory injury rather than viral replication, and apoptosis activator LY294002 reversed FB1-promoted viral replication rather than inflammatory injury. Summarily, low-dose FB1 exposure aggravated CIV-induced inflammatory injury and viral replication in vivo and in vitro via mTORC1-triggered apoptosis-pyroptosis shift. Our study provided new sights into the influence of mycotoxin on the virus-host interaction and the CIV control.

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“…In the classical pyroptosis pathway, when certain inflammasomes (NLRP1, NLRP3, NLRC4, and AIM2) stimulate pyroptosis-related pattern recognition receptors, they recruit and activate CASP1 either directly or by recruiting the receptor protein ASC recruits and activates CASP1, which successively promotes the maturation of IL-1β and IL-18 precursors and cleaves GSDMD [ 10 ]. Among other pyroptosis pathways, activated CASP4/5 specifically cleaves GSDMD [ 43 ], as well as CASP8 and CASP9 by affecting CASP3, causing cleavage of GSDME [ 44 , 45 ]. Subsequently, pyroptosis pathways mediated by cleavage of other GSDM family proteins were identified, including GSDMA, GSDMB, and GSDMC [ 24 , 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Systematic transcriptome profiling of pyroptosis related signature for predicting prognosis and immune landscape in lower grade glioma

Gong

et al. 2022

BMC Cancer

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Background Pyroptosis is a programmed cell death mediated by the gasdermin superfamily, accompanied by inflammatory and immune responses. Exogenously activated pyroptosis is still not well characterized in the tumor microenvironment. Furthermore, whether pyroptosis-related genes (PRGs) in lower-grade glioma (LGG) may be used as a biomarker remains unknown. Methods The RNA-Sequencing and clinical data of LGG patients were downloaded from publicly available databases. Bioinformatics approaches were used to analyze the relationship between PRGs and LGG patients’ prognosis, clinicopathological features, and immune status. The NMF algorithm was used to differentiate phenotypes, the LASSO regression model was used to construct prognostic signature, and GSEA was used to analyze biological functions and pathways. The expression of the signature genes was verified using qRT-PCR. In addition, the L1000FWD and CMap tools were utilized to screen potential therapeutic drugs or small molecule compounds and validate their effects in glioma cell lines using CCK-8 and colony formation assays. Results Based on PRGs, we defined two phenotypes with different prognoses. Stepwise regression analysis was carried out to identify the 3 signature genes to construct a pyroptosis-related signature. After that, samples from the training and test cohorts were incorporated into the signature and divided by the median RiskScore value (namely, Risk-H and Risk-L). The signature shows excellent predictive LGG prognostic power in the training and validation cohorts. The prognostic signature accurately stratifies patients according to prognostic differences and has predictive value for immune cell infiltration and immune checkpoint expression. Finally, the inhibitory effect of the small molecule inhibitor fedratinib on the viability and proliferation of various glioma cells was verified using cell biology-related experiments. Conclusion This study developed and validated a novel pyroptosis-related signature, which may assist instruct clinicians to predict the prognosis and immunological status of LGG patients more precisely. Fedratinib was found to be a small molecule inhibitor that significantly inhibits glioma cell viability and proliferation, which provides a new therapeutic strategy for gliomas.

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Apoptin induces pyroptosis of colorectal cancer cells via the GSDME-dependent pathway

Cited by 44 publications

References 42 publications

Osthole Induces Apoptosis and Caspase-3/GSDME-Dependent Pyroptosis via NQO1-Mediated ROS Generation in HeLa Cells

Osthole Induces Apoptosis and Caspase-3/GSDME-Dependent Pyroptosis via NQO1-Mediated ROS Generation in HeLa Cells

Fumonisin B1 aggravates inflammatory injury via mTORC1/pyroptosis, while promotes viral replication via mTORC1/apoptosis in Canine influenza virus-infected mice and A549 cells

Systematic transcriptome profiling of pyroptosis related signature for predicting prognosis and immune landscape in lower grade glioma

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