Defective pyroptosis

Stable Identifier
Homo sapiens
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Pyroptosis is a form of lytic inflammatory programmed cell death that is mediated by the pore‑forming gasdermins (GSDMs) (Shi J et al. 2017) to stimulate immune responses through the release of pro‑inflammatory interleukin (IL)‑1β, IL‑18 (mainly in GSDMD-mediated pyroptosis) as well as danger signals such as adenosine triphosphate (ATP) or high mobility group protein B1 (HMGB1) (reviewed in Shi J et al. 2017; Man SM et al. 2017; Tang D et al. 2019; Lieberman J et al. 2019). Pyroptosis protects the host from microbial infection but can also lead to pathological inflammation if overactivated or dysregulated (reviewed in Orning P et al. 2019; Tang L et al. 2020). During infections, the excessive production of cytokines can lead to a cytokine storm, which is associated with acute respiratory distress syndrome (ARDS) and systemic inflammatory response syndrome (SIRS) (reviewed in Tisoncik JR et al. 2012; Karki R et al. 2020; Ragab D et al. 2020). Pyroptosis has a close but complicated relationship to tumorigenesis, affected by tissue type and genetic background. Pyroptosis can trigger potent antitumor immune responses or serve as an effector mechanism in antitumor immunity (Wang Q et al. 2020; Zhou Z et al. 2020; Zhang Z et al. 2020), while in other cases, as a type of proinflammatory death, pyroptosis can contribute to the formation of a microenvironment suitable for tumor cell growth (reviewed in Xia X et al. 2019; Jiang M et al. 2020; Zhang Z et al. 2021).

This Reactome module describes the defective GSDME function caused by cancer‑related GSDME mutations (Zhang Z et al. 2020). It also shows epigenetic inactivation of GSDME due to hypermethylation of the GSDME promoter region (Akino K et al. 2007; Kim MS et al. 2008a,b; Croes L et al. 2017, 2018; Ibrahim J et al. 2019). Aberrant promoter methylation is considered to be a hallmark of cancer (Ehrlich M et al. 2002; Dong Y et al. 2014; Lam K et al. 2016; Croes L et al. 2018). Treatment with the DNA methyltransferase inhibitor decitabine (5‑aza‑2'‑deoxycytidine or DAC) may elevate GSDME expression in certain cancer cells (Akino K et al. 2007; Fujikane T et al. 2009; Wang Y et al. 2017).

Literature References
PubMed ID Title Journal Year
30993897 Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer

Ibrahim, J, Op de Beeck, K, Fransen, E, Croes, L, Beyens, M, Suls, A, Vanden Berghe, W, Peeters, M, Van Camp, G

Cancer Med 2019
32188940 Gasdermin E suppresses tumour growth by activating anti-tumour immunity

Zhang, Z, Zhang, Y, Xia, S, Kong, Q, Li, S, Liu, X, Junqueira, C, Meza-Sosa, KF, Mok, TMY, Ansara, J, Sengupta, S, Yao, Y, Wu, H, Lieberman, J

Nature 2020
33033617 Emerging insights on the role of gasdermins in infection and inflammatory diseases

Tang, L, Lu, C, Zheng, G, Burgering, BM

Clin Transl Immunology 2020
Name Identifier Synonyms
breast carcinoma DOID:3459 Mammary carcinoma, carcinoma of breast
gastric adenocarcinoma DOID:3717 adenocarcinoma of stomach (disorder), stomach adenocarcinoma
lung adenocarcinoma DOID:3910 nonsmall cell adenocarcinoma
colon adenocarcinoma DOID:234 adenocarcinoma of the colon, adenocarcinoma of colon, Colonic adenocarcinoma
melanoma DOID:1909 Naevocarcinoma, melanoma, melanoma, malignant melanoma, morphology (morphologic abnormality), malignant melanoma NOS (morphologic abnormality), malignant melanoma (disorder), malignant melanoma, malignant melanoma, malignant melanoma, malignant melanoma
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
head and neck squamous cell carcinoma DOID:5520 carcinoma of the head and neck, squamous cell carcinoma of the head and neck
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