Simvastatin Suppresses Proliferation and Migration in Non-small Cell Lung Cancer via Pyroptosis

Wang, Fengjiao; Liu, Wei; Ning, Jinfeng; Wang, Junfeng; Lang, Yaoguo; Jin, Xiangyuan; Zhu, Kaibin; Wang, Xiuyun; Li, Xiaoguang; Yang, Fan; Ma, Jianqun; Xu, Shidong

doi:10.7150/ijbs.23542

Cited by 103 publications

(88 citation statements)

References 24 publications

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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%

“…Furthermore, some chemicals were reported to suppress the proliferation of NSCLC cells via the activation of pyroptosis. 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].…”

Section: Discussionmentioning

confidence: 99%

“…These imaging results clearly indicate that PPVI-induced A549 cells underwent an apoptosis-to-pyroptosis switch, and, ultimately, lytic cell death. Moreover, we also used annexin V-FITC/PI together with flow cytometry to analyze the percentage of cell viability, early apoptosis, late apoptosis, and the pyroptosis of A549 and H1299 cells after being treated by PPVI for 24 h. Similar concentrations of PPVI were used and the results showed that PPVI significantly and dose-dependently increased the rate of pyroptotic cells, and correspondingly decreased the cell viability of A549 and H1299 cells ( Figure 2D,E) [31]. Taken together, the above results suggested that PPVI significantly induced lytic cell death (pyroptosis) in A549 and H1299 cells.…”

Section: Ppvi Induces Distinct Patterns Of Apoptosis and Lytic Cell Dmentioning

confidence: 98%

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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

231

146

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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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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Ppvi Induces Distinct Patterns Of Apoptosis and Lytic Cell Dmentioning

confidence: 98%

See 1 more Smart Citation

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

231

146

View full text Add to dashboard Cite

show abstract

“…Recent studies have revealed the roles of pyroptosis in several types of cancers, including colon cancer, gastric cancer, lung cancer, breast cancer, liver cancer, and glioma. However, no studies have focused on the pyroptosis in PDAC (18)(19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

MST1 Suppresses Pancreatic Cancer Progression via ROS-Induced Pyroptosis

Cui

Zhou

Yang

et al. 2019

Molecular Cancer Research

104

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Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, and its incidence is increasing annually. It is critical to reveal and delineate the molecular mechanism promoting PDAC development and progression. Mammalian STE20-like kinase 1 (MST1) is a proapoptotic cytoplasmic kinase and also one of the core components of the Hippo pathway. Here, we showed that MST1 expression was decreased in PDAC, and restored expression of MST1 promoted PDAC cell death and suppressed the proliferation, migration, invasion, and cell spheroid formation of PDAC via caspase-1-induced pyroptosis. Further studies demonstrated that pyroptosis induced by MST1 was independent of the Hippo pathway, but mediated by reactive oxygen species (ROS). And ROS scavenger N-acetyl-cysteine attenuated the activation of caspase-1 induced by MST1 and the effect of MST1 in PDAC cell death, proliferation, migration, and invasion. Collectively, our study demonstrated that MST1 suppressed the progression of PDAC cells at least partly through ROS-induced pyroptosis.Implications: In this study, we identified a new mechanism of MST1 in inhibiting PDAC development and progression and revealed that MST1 would be a potential prognostic and therapeutic target for PDAC.

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“…Previous studies have demonstrated that pyroptosis aggravates hepatic fibrosis diabetes and diabetic cardiomyopathy 25,26 . A recent study of tumor cells showed that induction of caspase-1-mediated pyroptosis by simvastatin in non-small-cell lung cancer (NSCLC) promoted cell death and exerted antitumor effects 27 . Caspase-1 is downregulated in many cancer types, and its loss enhances tumor formation and promotes cancer development 27,28 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of BRD4 prevents proliferation and epithelial–mesenchymal transition in renal cell carcinoma via NLRP3 inflammasome-induced pyroptosis

et al. 2020

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BRD4 has long been implicated in many different pathological processes, in particular, the development of cancer and inflammation. Pyroptosis is a newly recognized type of inflammatory programmed cell death. However, the correlation between BRD4 and pyroptosis in renal cell carcinoma (RCC) remains elusive. The present study demonstrates that BRD4 expression levels are markedly upregulated, while pyroptosis-associated proteins are significantly reduced, in RCC tissues and cells. Inhibition of BRD4, via either genetic knockdown or use of bromodomain inhibitor JQ1, prevented cell proliferation and epithelial-mesenchymal transition (EMT) progression and induced caspase-1dependent pyroptosis in RCC both in vitro and in vivo. In addition, BRD4 inhibition suppressed proliferation and EMT though pyroptosis in vitro and in vivo. Moreover, NLRP3, which mediates caspase-1-dependent pyroptosis, was increased upon BRD4 inhibition. Furthermore, the transcriptional activity of NLRP3 was enhanced by BRD4 inhibition, and this enhancement was blocked by activation of NF-κB phosphorylation, indicating that NF-κB is an upstream regulator of NLRP3. Collectively, these results show that BRD4 inhibition prevents cell proliferation and EMT, and exerts an antitumor effect in RCC by activating the NF-κB-NLRP3-caspase-1 pyroptosis signaling pathway. Thus, BRD4 is a potential target for RCC treatment, and JQ1 shows promise as a therapeutic agent for this disease.

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Simvastatin Suppresses Proliferation and Migration in Non-small Cell Lung Cancer via Pyroptosis

Cited by 103 publications

References 24 publications

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

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

MST1 Suppresses Pancreatic Cancer Progression via ROS-Induced Pyroptosis

Inhibition of BRD4 prevents proliferation and epithelial–mesenchymal transition in renal cell carcinoma via NLRP3 inflammasome-induced pyroptosis

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