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Review
. 2022 Nov 29:12:1013544.
doi: 10.3389/fonc.2022.1013544. eCollection 2022.

Pyroptosis: A new insight of non-small-cell lung cancer treatment

Xi Chen  1 , Jianzhang Wu  2 , Jiabing Wang  3
Affiliations
Review

Pyroptosis: A new insight of non-small-cell lung cancer treatment

Xi Chen et al. Front Oncol. .

Abstract

Non-small cell lung cancer (NSCLC) has become one of the most common malignant tumors. Emerging evidence has shown that tumor resistance to apoptosis by damaging or bypassing apoptotic cell death is a major contributor to poor responses to therapy in patients with NSCLC. Pyroptosis is a new type of cytolytic and inflammatory programmed death distinct from apoptosis. Currently, pyroptosis has been reported to cause a strong inflammatory response and significant tumor suppression. It is considered a promising therapeutic strategy and prognosis for NSCLC. In this review, we summarized the characteristics of pyroptosis from its underlying basis and role in NSCLC, thereby providing the potential of pyroptosis as a therapeutic strategy and highlighting the challenges of activating pyroptosis in NSCLC treatment.

Keywords: NSCLC; prognosis; programmed cell death; pyroptosis; therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The key events in the history of pyroptosis.
Figure 2
Figure 2
Molecular mechanism of gasdermins-mediated pyroptosis. In classical pathway, PAMPs and DAMPs are recognized by various stimuli and then activate conformational change of the NLRP3 inflammasome, and NLRP3 recruits ASC and binds to pro-caspase-1 to form NLRP3- ASC-pro-caspase-1 protein complex, which then cleaves pro-caspase-1 into caspase-1. Activated caspase-1 destroys the intramolecular auto-inhibitory structure of GSDMD by cleaving GSDMD, which promotes GSDMD-NT generation and induces pyroptosis. Caspase-1 can also recognize and catalyze pro-IL-1β, pro-IL-18, leading to maturation of IL-1β, IL-18. In the noncanonical pathway, caspase-4/5/11 are recognized by LPS from Gram-negative bacteria in the cytoplasm, which then lead to pyroptosis by cleaving GSDMD. Inhibiting TAK1 can stimulate the activation of caspase-8, which cleaves GSDMD and causes pyroptosis. An elastase and cathepsin G can also cleave GSDMD and activates pyroptosis. ESCRT-III complex repairs the membrane by removing the GSDMD pore through exocytosis. Caspase-3, caspase-7 and enterovirus 71 3C cleave the GSDMD and generate a nonfunctional N-terminus. Under the action of chemotherapy, radiation and GzmB, caspase-3 was activated and cleaves GSDME to liberate the cytotoxic N-GSDME, inducing pyroptosis. 2-BP can reverse caspase-3/GSDME-mediated pyroptosis. In addition, GSDMB is cleaved by GzmA, while under hypoxia conditions, GSDMC is cleaved by TNFα-activated-caspase-8 and transcriptionally upregulated through pSTAT3 interaction with PD-L1. SpeB directly activates GSDMA and induce pyroptosis. Abbreviations: DAMPs, danger-associated molecular patterns; PAMPs, pathogen associated molecular patterns; ASC, apoptosis-associated speck-like protein contain a CARD; LPS, lipopolysaccharides; NLRP3, NLR family pyrin domain-containing 3; TAK1, transforming growth factor beta-activated kinase 1; LDH, lactate dehydrogenase; HMGB1, high-mobility group box 1; IL, interleukin; TAK1, transforming growth factor beta-activated kinase 1. ESCRT, endosomal sorting complex required for transport; GzmA/B, granzyme A/B; 2-BP, 2-bromopalmitate; SpeB, streptococcal pyrogenic exotoxin B; pSTAT3, phospho-signal transducer and activator of transcription 3; PD-L1, programmed death-ligand 1.
Figure 3
Figure 3
The possible mechanism of targeting pyroptosis in NSCLC.
See this image and copyright information in PMC

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