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
32188940 Gasdermin E suppresses tumour growth by activating anti-tumour immunity

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

Nature 2020
30993897 Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer

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

Cancer Med 2019
33033617 Emerging insights on the role of gasdermins in infection and inflammatory diseases

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

Clin Transl Immunology 2020
Name Identifier Synonyms
gastric adenocarcinoma DOID:3717 adenocarcinoma of stomach (disorder), stomach adenocarcinoma
breast carcinoma DOID:3459 Mammary carcinoma, carcinoma of breast
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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