Pyroptosis is an inflammatory form of programmed cell death that is mediated by pore-forming proteins such as the gasdermin family (GSDMs), including GSDMA-E. Upon cleavage by activated caspases or granzyme proteases, the N-terminal of GSDMs oligomerizes in membranes to form pores, resulting in pyroptosis. Though all the gasdermin proteins have been studied in cancer, the role of pyroptosis in cancer remains mysterious, with conflicting findings. Numerous studies have shown that various stimuli, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and chemotherapeutic drugs, could trigger pyroptosis when the cells express GSDMs. However, it is not clear whether pyroptosis in cancer induced by chemotherapeutic drugs or CAR T cell therapy is beneficial or harmful for anti-tumor immunity. This review discusses the discovery of pyroptosis as well as its role in inflammatory diseases and cancer, with an emphasis on tumor immunity.

https://www.mdpi.com/2072-6694/13/14/3620/pdf

Pyroptosis in Cancer: Friend or Foe?

Background IL27 has been reported to play dual roles in cancer; however, its effects on the tumor microenvironment (TME), immunotherapy, and prognosis in melanoma remain largely unclear. This study was aimed to uncover the effects of IL27 on TME, immunotherapy and prognosis in patients with melanoma. Methods RNA-seq data, drug sensitivity data, and clinical data were obtained from TCGA, GEO, CCLE, and CTRP. Log-rank test was used to determine the survival value of IL27. Univariate and multivariate Cox regression analyses were employed to determine the independent predictors of survival outcomes. DAVID and GSEA were used to perform gene set functional annotations. ssGSEA was used to explore the association between IL27 and immune infiltrates. ConsensusClusterPlus was used to classify melanoma tissues into hot tumors or cold tumors. Results Clinically, IL27 was negatively correlated with Breslow depth (P = 0.00042) and positively associated with response to radiotherapy (P = 0.038). High IL27 expression showed an improved survival outcome (P = 0.00016), and could serve as an independent predictor of survival outcomes (hazard ratio: 0.32 - 0.88, P = 0.015). Functionally, elevated IL27 expression could induce an enhanced immune response and pyroptosis (R = 0.64, P = 1.2e-55), autophagy (R = 0.37, P = 7.1e-17) and apoptosis (R = 0.47, P = 1.1e-27) in patients with melanoma. Mechanistically, elevated IL27 expression was positively correlated with cytotoxic cytokines (including INFG and GZMB), enhanced immune infiltrates, and elevated CD8/Treg ratio (R = 0.14, P = 0.02), possibly driving CD8+ T cell infiltration by suppressing β-catenin signaling in the TME. Furthermore, IL27 was significantly associated with hot tumor state, multiple predictors of response to immunotherapy, and improved drug response in patients with melanoma. Conclusions IL27 was correlated with enriched CD8+ T cells, desirable therapeutic response and improved prognosis. It thus can be utilized as a promising modulator in the development of cytokine-based immunotherapy for melanoma.

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Integrative Characterization of the Role of IL27 In Melanoma Using Bioinformatics Analysis.

Cadmium exposure induces pyroptosis in testicular tissue by increasing oxidative stress and activating the AIM2 inflammasome pathway.

Urinary malignancies refer to a series of malignant tumors that occur in the urinary system and mainly include kidney, bladder, and prostate cancers. Although local or systemic radiotherapy and chemotherapy, immunotherapy, castration therapy and other methods have been applied to treat these diseases, their high recurrence and metastasis rate remain problems for patients. With in-depth research on the pathogenesis of urinary malignant tumors, this work suggests that regulatory cell death (RCD) plays an important role in their occurrence and development. These RCD pathways are stimulated by various internal and external environmental factors and can induce cell death or permit cell survival under the control of various signal molecules, thereby affecting tumor progression or therapeutic efficacy. Among the previously reported RCD methods, necroptosis, pyroptosis, ferroptosis, and neutrophil extracellular traps (NETs) have attracted research attention. These modes transmit death signals through signal molecules, such as cysteine-aspartic proteases (caspase) family and tumor necrosis factor-α (TNF-α) that have a wide and profound influence on tumor proliferation or death and even change the sensitivity of tumor cells to therapy. This review discussed the effects of necroptosis, pyroptosis, ferroptosis, and NETs on kidney, bladder and prostate cancer and summarized the latest research and achievements in these fields. Future directions and possibility of improving the denouement of urinary system tumors treatment by targeting RCD therapy were also explored.

Regulated Cell Death in Urinary Malignancies

Cadmium (Cd) exposure can cause multiple organ damage in humans and animals by causing oxidative stress. Organic selenium can antagonize the toxic damage of heavy metals by exerting antioxidant effects. Oxidative stress can activate NLRP3/Caspase1-dependent pyroptosis, but it is not clear whether yeast selenium (Se Y) can antagonize Cd-induced pyroptosis in the chicken liver. In this experiment, we studied the effects of CdCl2 single, Se Y single, and combined exposure on the pyroptosis of chicken liver. The results showed that Cd exposure induced oxidative stress in the chicken liver, and the expression of Sepx1, SelU, SelT, GPx1, GPx4, Dio1, Dio2, Dio3, TrxR1, TrxR2, TrxR3, SelH, SelI, SelO, SelK, SelPb, Selpp, and Sel15 decreased. In addition, NLRP3 inflammasome complex (NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing (ASC), and pro-Caspase1), Cysteinyl aspartate specific proteinase (Caspase1), Interleukin-β (IL-1β), and Interleukin-18 (IL-18) were upregulated. The combined treatment of Se Y and Cd found that the antioxidant level and the expression level of selenoprotein recovered to the Se group, and the liver pyroptosis decreased. Principal component analysis and correlation analysis screened out that selenoprotein O (SelO) is negatively correlated with pyroptosis-related genes. In short, our data shows that Se Y exerts an antioxidant effect by increasing the expression of selenoproteins and antagonizing the pyroptosis of chicken liver induced by Cd. This study provides new ideas for the field of heavy metal toxicology research. And the selected SelO has an important reference significance for follow-up research.

Yeast Selenium Exerts an Antioxidant Effect by Regulating the Level of Selenoprotein to Antagonize Cd-Induced Pyroptosis of Chicken Liver.

Acute cadmium exposure induces GSDME-mediated pyroptosis in triple-negative breast cancer cells through ROS generation and NLRP3 inflammasome pathway activation.

Transformer 2 alpha homolog (TRA2A), a member of the serine/arginine-rich splicing factor family, has been shown to control mRNA splicing in development and cancers. However, it remains unclear whether TRA2A is involved in lncRNA regulation. In the present study, we found that TRA2A was upregulated and correlated with poor prognosis in esophageal cancer. Downregulation of TRA2A suppressed the tumor growth in xenograft nude mice. Epitranscriptomic microarray showed that depletion of TRA2A affected global lncRNA methylation similarly to the key m6 A methyltransferase, METTL3, by silencing. MeRIP-qPCR, RNA pull-down, CLIP analyses, and stability assays indicated that ablation of TRA2A reduced m6 A-modification of the oncogenic lncRNA MALAT1, thus inducing structural alterations and reduced stability. Furthermore, Co-IP experiments showed TRA2A directly interacted with METTL3 and RBMX, which also affected the writer KIAA1429 expression. Knockdown of TRA2A inhibited cell proliferation in a manner restored by RBMX/KIAA1429 overexpression. Clinically, MALAT1, RBMX, and KIAA1429 were prognostic factors of worse survival in ESCA patients. Structural similarity-based virtual screening in FDA-approved drugs repurposed nebivolol, a β1 -adrenergic receptor antagonist, as a potent compound to suppress the proliferation of esophageal cancer cells. Cellular thermal shift and RIP assay indicated that nebivolol may compete with MALAT1 to bind TRA2A. In conclusion, our study revealed the noncanonical function of TRA2A, which coordinates with multiple methylation proteins to promote oncogenic MALAT1 during ESCA carcinogenesis.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/cas.15870

Mingrong Bei

Papers

Acute cadmium exposure induces GSDME-mediated pyroptosis in triple-negative breast cancer cells through ROS generation and NLRP3 inflammasome pathway activation.

Splicing factor TRA2A contributes to esophageal cancer progression via a noncanonical role in lncRNA m6 A methylation.