Caspase‐3‐mediated GSDME induced Pyroptosis in breast cancer cells through the ROS/JNK signalling pathway
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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.Keywords:
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Pyroptosis is a lytic form of cell death distinguished from apoptosis, ferroptosis, necrosis, necroptosis, NETosis, oncosis, pyronecrosis and autophagy. Proinflammatory caspases cleave a gasdermin D (GSDMD) protein to generate a 31 kDa N-terminal domain. The cleavage relieves the intramolecular inhibition on the gasdermin-N domain, which then moves to the plasma membrane to exhibit pore-forming activity. Thus, GSDMD acts as the final and direct executor of pyroptotic cell death. Owing to the selective targeting of the inner leaflet of the plasma membrane with the pore-forming that determines pyroptotic cell death, GSDMD could be a potential target to control cell death or extracellular bacterial infections. Intriguingly, other gasdermin family members also share similar N-terminal domains, but they present different cell death programs. Herein, we summarize features and functions of the novel player proteins in cell death, including GSDMD triggering pyroptosis, Gsdma3/GSDMA initiating autophagy/apoptosis and DFNA5 inducing apoptosis/secondary necrosis. The gasdermin N terminus appears to be a novel pore-forming protein. This provides novel insight into the underlying roles and mechanisms of lytic or nonlytic forms of programmed cell death, as well as their potential applications in inflammation-associated diseases.
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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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Apoptosis is a prototype of regulated cell death and plays a crucial role in the development of various organs and maintaining tissue homeostasis. Recent studies have revealed that new types of regulated cell death, including necroptosis, ferroptosis, and pyroptosis are molecularly identified. In this review, we discuss the molecular mechanisms and the functions of new types of regulated cell death.
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Pyroptosis is a newly discovered proinflammatory form of programmed cell death. Pyroptosis, which depends on cysteinyl aspartate specific proteinase-1(caspase-1), is inherently the proinflammatory response of the cell.Triggered by various pathological stimuli, pyroptosis is crucial for controlling virus infections.Despite that there are similarities between pyroptosis and necrosis(or apoptosis), there are apparent differences.This review discusses the feature of pyroptosis and the viruses which induce or inhibit pyroptosis.
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Pyroptosis; Inflammasome; Caspase-1; IL-1β; IL-18
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The gasdermins (GSDM), a family of pore-forming proteins, consist of gasdermin A (GSDMA), gasdermin B (GSDMB), gasdermin C (GSDMC), gasdermin D (GSDMD), gasdermin E (GSDME) and DFNB59 (Pejvakin (PJVK)) in humans. These proteins play an important role in pyroptosis. Among them, GSDMD is the most extensively studied protein and is identified as the executioner of pyroptosis. Other family members have also been implicated in certain cancers. As a unique form of programmed cell death, pyroptosis is closely related to tumor progression, and the inflammasome, an innate immune mechanism that induces inflammation and pyroptosis. In this review, we explore the current developments of pyroptosis, the inflammasome, and especially we review the gasdermin family members and their role in inducing pyroptosis and the possible therapeutic values in antitumor effects.
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调查 CQ11 的颠倒效果的目的，氯奎衍生物，在上多在 doxorubicin (纪录影片) 的药抵抗(MDR ) 抵抗的人的胸癌房间线 MCF/DOX。一根人的乳癌房间线， MCF，和它的纪录影片抵抗的变体的方法房间， MCF/DOX，与纪录影片和 /or CQ11 被栽培。药在试管内的细胞毒性是由 MTT 方法的 assayed。在这些房间的纪录影片的累积被荧光分光光度计检测。结果 MCF/DOX 房间是对与 MCF 房间比较的纪录影片更抵抗的 119 次。在有在 1.0 ， 2.5 和 5.0 μmol/L 的集中的 CQ11 的同时的治疗以后，为 MCF/DOX 房间的纪录影片的 IC50 从 3.1 ± 减少了 0.47 μmol/L 到 0.58 ± 0.032 ， 0.19 ± 0.012 和 0.081 ± 0.015 μmol/L ，分别地这样，由5.3褶层增加 DOX 敏感( P < 0.01 )，16褶层( P < 0.01 )并且38褶层( P < 0.01 )分别地。在纪录影片的累积试金，有 CQ11 的 MCF/DOX 房间的同时的孵化显著地在 MCF/DOX 房间增加了 DOX 累积。没有如此的结果在父母 MCF 房间被发现。结论 CQ11 由在 MCF/DOX 房间提高细胞内部的纪录影片累积有强壮的 MDR 颠倒效果，显示 CQ11 可以是有希望的 MDR chemosensitivity。
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Pyroptosis is a form of regulated cell death that is characterized by gasdermin processing and increased membrane permeability. Caspase-1 and caspase-11 have been considered to be essential for gasdermin D processing associated with inflammasome activation. In the present study, we found that NLRP3 inflammasome activation induces delayed necrotic cell death via ASC in caspase-1/11-deficient macrophages. Furthermore, ASC-mediated caspase-8 activation and subsequent gasdermin E processing are necessary for caspase-1-independent necrotic cell death. We define this necrotic cell death as incomplete pyroptosis because IL-1β release, a key feature of pyroptosis, is absent, whereas IL-1α release is induced. Notably, unprocessed pro-IL-1β forms a molecular complex to be retained inside pyroptotic cells. Moreover, incomplete pyroptosis accompanied by IL-1α release is observed under the pharmacological inhibition of caspase-1 with VX765. These findings suggest that caspase-1 inhibition during NLRP3 inflammasome activation modulates forms of cell death and permits the release of IL-1α from dying cells.
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