The role of pyroptosis in cancer: pro-cancer or pro-“host”?

Xia, Xiaojing; Wang, Xin; Cheng, Zhe; Qin, Wanhai; Lei, Liancheng; Jiang, Jinqing; Hu, Jianhe

doi:10.1038/s41419-019-1883-8

Cited by 645 publications

(702 citation statements)

References 125 publications

(164 reference statements)

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“…GSDMC functioned as an oncogene, enhancing cell proliferation and tumorigenesis in lung adenocarcinoma and colorectal carcinogenesis ( Miguchi et al, 2016 ; Wei et al, 2020 ). It presented high in malignant melanoma but undetectable in normal epithelial cells, which might be associated with the metastasis of cells ( Xia et al, 2019 ). CSTA, one of the tumor suppressors, had the anti-apoptotic effect and maintaining cell-cell adhesion.…”

Section: Discussionmentioning

confidence: 99%

Identification of Signatures of Prognosis Prediction for Melanoma Using a Hypoxia Score

Shou

Yang

et al. 2020

Front. Genet.

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Melanoma is one of the most aggressive cancers. Hypoxic microenvironment affects multiple cellular pathways and contributes to tumor progression. The purpose of the research was to investigate the association between hypoxia and melanoma, and identify the prognostic value of hypoxia-related genes. Based on the GSVA algorithm, gene expression profile collected from The Cancer Genome Atlas (TCGA) was used for calculating the hypoxia score. The Kaplan–Meier plot suggested that a high hypoxia score was correlated with the inferior survival of melanoma patients. Using differential gene expression analysis and WGCNA, a total of 337 overlapping genes associated with hypoxia were determined. Protein-protein interaction network and functional enrichment analysis were conducted, and Lasso Cox regression was performed to establish the prognostic gene signature. Lasso regression showed that seven genes displayed the best features. A novel seven-gene signature (including ABCA12, PTK6, FERMT1, GSDMC, KRT2, CSTA, and SPRR2F) was constructed for prognosis prediction. The ROC curve inferred good performance in both the TCGA cohort and validation cohorts. Therefore, our study determined the prognostic implication of the hypoxia score in melanoma and showed a novel seven-gene signature to predict prognosis, which may provide insights into the prognosis evaluation and clinical decision making.

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Section: Discussionmentioning

confidence: 99%

Identification of Signatures of Prognosis Prediction for Melanoma Using a Hypoxia Score

Shou

Yang

et al. 2020

Front. Genet.

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“…As can be seen from the above, GSDME-mediated pyroptosis can kill tumor cells. Some scholars have suggested that during the treatment of malignant tumors, appropriate chemotherapeutic drugs can be selected according to the expression of GSDME, thereby increasing the sensitivity to chemotherapeutic drugs, enhancing the anti-tumor immunity and reducing drug resistance 74 . However, some scholars also proposed that the high expression of GSDME would enhance the side effects of chemotherapy.…”

Section: High-level Gsdme Increased the Side Effect Of Chemotherapymentioning

confidence: 99%

“…When bleomycin was administered to mice, WT mice developed more severe lung injury and inflammation than GSDME −/− mice. GSDME-mediated pyroptosis can kill normal cells and increase the adverse effect of chemotherapy 5 , 36 , 74 . So, how to avoid the side effects of GSDME in the treatment of cancer is the focus of the next step.…”

Section: High-level Gsdme Increased the Side Effect Of Chemotherapymentioning

confidence: 99%

The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

et al. 2020

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Apoptosis has long been recognized as a mechanism that kills the cancer cells by cytotoxic drugs. In recent years, studies have proved that pyroptosis can also shrink tumors and inhibit cells proliferation. Both apoptosis and pyroptosis are caspase-dependent programmed cell death pathways. Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death. When GSDME is highly expressed, the active caspase-3 cuts it and releases the N-terminal domain to punch holes in the cell membrane, resulting in cell swelling, rupture, and death. When the expression of GSDME is low, it will lead to the classical mechanism of tumor cell death, which is apoptosis. More interestingly, researchers have found that GSDME can also be located upstream of caspase-3, connecting extrinsic, and intrinsic apoptotic pathways. Then, promoting caspase-3 activation, and forming a self-amplifying feed-forward loop. GSDME-mediated pyroptosis is correlated with the side effects of chemotherapy and anti-tumor immunity. This article mainly reviews the caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer, to provide new strategies and targets for cancer treatment.

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“…The relationship between pyroptosis and cancer is context dependent and complex. Pyroptosis may be capable of being either pro- or anti-cancer [ 71 ]. On one hand, the release of inflammatory mediators and induction of hyperactive signaling pathways may promote tumorigenesis and lead to drug resistance.…”

Section: Resultsmentioning

confidence: 99%

A Small Molecule Stabilizer of the MYC G4-Quadruplex Induces Endoplasmic Reticulum Stress, Senescence and Pyroptosis in Multiple Myeloma

Gaikwad

Phyo

Arteaga

et al. 2020

Cancers

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New approaches to target MYC include the stabilization of a guanine-rich, G-quadruplex (G4) tertiary DNA structure in the NHE III region of its promoter. Recent screening of a small molecule microarray platform identified a benzofuran, D089, that can stabilize the MYC G4 and inhibit its transcription. D089 induced both dose- and time-dependent multiple myeloma cell death mediated by endoplasmic reticulum induced stress. Unexpectedly, we uncovered two mechanisms of cell death: cellular senescence, as evidenced by increased levels of p16, p21 and γ-H2AX proteins and a caspase 3-independent mechanism consistent with pyroptosis. Cells treated with D089 exhibited high levels of the cleaved form of initiator caspase 8; but failed to show cleavage of executioner caspase 3, a classical apoptotic marker. Cotreatment with the a pan-caspase inhibitor Q-VD-OPh did not affect the cytotoxic effect of D089. In contrast, cleaved caspase 1, an inflammatory caspase downstream of caspases 8/9, was increased by D089 treatment. Cells treated with D089 in addition to either a caspase 1 inhibitor or siRNA-caspase 1 showed increased IC50 values, indicating a contribution of cleaved caspase 1 to cell death. Downstream effects of caspase 1 activation after drug treatment included increases in IL1B, gasdermin D cleavage, and HMGB1 translocation from the nucleus to the cytoplasm. Drug treated cells underwent a ‘ballooning’ morphology characteristic of pyroptosis, rather than ‘blebbing’ typically associated with apoptosis. ASC specks colocalized with NLRP3 in proximity ligation assays after drug treatment, indicating inflammasome activation and further confirming pyroptosis as a contributor to cell death. Thus, the small molecule MYC G4 stabilizer, D089, provides a new tool compound for studying pyroptosis. These studies suggest that inducing both tumor senescence and pyroptosis may have therapeutic potential for cancer treatment.

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The role of pyroptosis in cancer: pro-cancer or pro-“host”?

Cited by 645 publications

References 125 publications

Identification of Signatures of Prognosis Prediction for Melanoma Using a Hypoxia Score

Identification of Signatures of Prognosis Prediction for Melanoma Using a Hypoxia Score

The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

A Small Molecule Stabilizer of the MYC G4-Quadruplex Induces Endoplasmic Reticulum Stress, Senescence and Pyroptosis in Multiple Myeloma

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