Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation

Zhang, Chengcheng; Li, Chenguang; Wang, Yaofeng; Xu, Lihui; He, Xian-Hui; Zeng, Qian; Zeng, Chengli; Mai, Feng-Yi; Hu, Bo; Ouyang, Dong-Yun

doi:10.1007/s10495-019-01515-1

Cited by 338 publications

(248 citation statements)

References 33 publications

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“…suggesting the important role of GSDME in the induction of pyroptosis, in agreement with previous studies 7, 51,52 . Although GSDME knockdown significantly decreased the LDH release and pyroptotic morphology, however, both were not completely diminished in our study, which might because GSDME was only about half knockeddown.…”

Section: Discussionsupporting

confidence: 93%

Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate

et al. 2020

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Many chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane permeabilization (MOMP), which induces the activation of pro-apoptotic caspase cascade. GSDME cleavage by the pro-apoptotic caspases determines whether chemotherapy drug treatments induce apoptosis or pyroptosis, however, its regulation mechanisms are not clear. In this study, we showed that TNFα+CHX and navitoclax-induced cancer cell pyroptosis through a BAK/BAX-caspase-3-GSDME signaling pathway. GSDME knockdown inhibited the pyroptosis, suggesting the essential role of GSDME in this process. Interestingly, GSDME was found to be palmitoylated on its C-terminal (GSDME-C) during chemotherapyinduced pyroptosis, while 2-bromopalmitate (2-BP) could inhibit the GSDME-C palmitoylation and chemotherapyinduced pyroptosis. Mutation of palmitoylation sites on GSDME also diminished the pyroptosis induced by chemotherapy drugs. Moreover, 2-BP treatment increased the interaction between GSDME-C and GSDME-N, providing a potential mechanism of this function. Further studies indicated several ZDHHC proteins including ZDHHC-2,7,11,15 could interact with and palmitoylate GSDME. Our findings offered new targets to achieve the transformation between chemotherapy-induced pyroptosis and apoptosis.

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Section: Discussionsupporting

confidence: 93%

Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate

et al. 2020

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“…Recent evidences suggested that multiple signaling pathways and various types of cell death may be activated in single dying cells [55,56], and ROS, as a trigger, can lead to various types of regulated cell death (RCD) [55,57,58]. Furthermore, these RCD share some common mechanisms [59], and many compounds, such as simvastatin, paclitaxel, cisplatin, etc., were reported to induce autophagy, apoptosis and pyroptosis in NSCLC [31,52,[60][61][62][63][64]. Therefore, we suspected that PPVI might also induce pyroptotic cell death in NSCLC via increased ROS levels.…”

Section: Discussionmentioning

confidence: 92%

“…For example, simvastatin suppresses proliferation and migration in vitro and in vivo by inducing pyroptosis via activating NLRP3-caspase-1-IL-1β and IL-18 pathways [31]. In addition, cisplatin was reported to induce higher levels of secondary necrosis/pyroptosis in A549 cells via the caspase-3/GSDME activation [52]. Therefore, the activation of caspase-1 plays an important role in inhibiting the proliferation of cancer cells, and the compounds with an activating NLRP3 inflammasome effect have the potential to be the treatments for NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer

Teng

Mei

Zhou

et al. 2020

Cancers

244

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Trillium tschonoskii Maxim (TTM), a traditional Chinese medicine, has been demonstrated to have a potent anti-tumor effect. Recently, polyphyllin VI (PPVI), a main saponin isolated from TTM, was reported by us to significantly suppress the proliferation of non-small cell lung cancer (NSCLC) via the induction of apoptosis and autophagy in vitro and in vivo. In this study, we further found that the NLRP3 inflammasome was activated in PPVI administrated A549-bearing athymic nude mice. As is known to us, pyroptosis is an inflammatory form of caspase-1-dependent programmed cell death that plays an important role in cancer. By using A549 and H1299 cells, the in vitro effect and action mechanism by which PPVI induces activation of the NLRP3 inflammasome in NSCLC were investigated. The anti-proliferative effect of PPVI in A549 and H1299 cells was firstly measured and validated by MTT assay. The activation of the NLRP3 inflammasome was detected by using Hoechst33324/PI staining, flow cytometry analysis and real-time live cell imaging methods. We found that PPVI significantly increased the percentage of cells with PI signal in A549 and H1299, and the dynamic change in cell morphology and the process of cell death of A549 cells indicated that PPVI induced an apoptosis-to-pyroptosis switch, and, ultimately, lytic cell death. In addition, belnacasan (VX-765), an inhibitor of caspase-1, could remarkably decrease the pyroptotic cell death of PPVI-treated A549 and H1299 cells. Moreover, by detecting the expression of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD in A549 and h1299 cells using Western blotting, immunofluorescence imaging and flow cytometric analysis, measuring the caspase-1 activity using colorimetric assay, and quantifying the cytokines level of IL-1β and IL-18 using ELISA, the NLRP3 inflammasome was found to be activated in a dose manner, while VX-765 and necrosulfonamide (NSA), an inhibitor of GSDMD, could inhibit PPVI-induced activation of the NLRP3 inflammasome. Furthermore, the mechanism study found that PPVI could activate the NF-κB signaling pathway via increasing reactive oxygen Cancers 2020, 12, 193 2 of 27 species (ROS) levels in A549 and H1299 cells, and N-acetyl-L-cysteine (NAC), a scavenger of ROS, remarkably inhibited the cell death, and the activation of NF-κB and the NLRP3 inflammasome in PPVI-treated A549 and H1299 cells. Taken together, these data suggested that PPVI-induced, caspase-1-mediated pyroptosis via the induction of the ROS/NF-κB/NLRP3/GSDMD signal axis in NSCLC, which further clarified the mechanism of PPVI in the inhibition of NSCLC, and thereby provided a possibility for PPVI to serve as a novel therapeutic agent for NSCLC in the future.

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“…On the other hand, resisting cell death is the important hallmark of cancers [19]. Induction of cancer cell pyroptosis by various stimulations can eliminate malignant cells [20][21][22][23][24]. Although pyroptotic death is often harmful to normal tissues, it can be beneficial to cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

Zheng

2020

IJMS

146

111

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Programmed Cell Death (PCD) is considered to be a pathological form of cell death when mediated by an intracellular program and it balances cell death with survival of normal cells. Pyroptosis, a type of PCD, is induced by the inflammatory caspase cleavage of gasdermin D (GSDMD) and apoptotic caspase cleavage of gasdermin E (GSDME). This review aims to summarize the latest molecular mechanisms about pyroptosis mediated by pore-forming GSDMD and GSDME proteins that permeabilize plasma and mitochondrial membrane activating pyroptosis and apoptosis. We also discuss the potentiality of pyroptosis as a therapeutic target in human diseases. Blockade of pyroptosis by compounds can treat inflammatory disease and pyroptosis activation contributes to cancer therapy.

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Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation

Cited by 338 publications

References 33 publications

Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate

Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate

Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer

Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

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