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

Xia et al. Cell Death and Disease (2019)10:650 https://doi.org/10.1038/s41419-019-1883-8 Cell Death & Disease REVIEW ARTICLE Open Access The role of pyroptosis in cancer: pro-cancer or pro-“host”? 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Xiaojing Xia 1 , Xin Wang2, Zhe Cheng1, Wanhai Qin3, Liancheng Lei4, Jinqing Jiang1 and Jianhe Hu1 Abstract Programmed cell death (PCD) refers to the way in which cells die depending on specific genes encoding signals or activities. Apoptosis, autophagy, and pyroptosis are all mechanisms of PCD. Among these mechanisms, pyroptosis is mediated by the gasdermin family, accompanied by inflammatory and immune responses. The relationship between pyroptosis and cancer is complex, and the effects of pyroptosis on cancer vary in different tissues and genetic backgrounds. On one hand, pyroptosis can inhibit the occurrence and development of tumors; on the other hand, as a type of proinflammatory death, pyroptosis can form a suitable microenvironment for tumor cell growth and thus promote tumor growth. In addition, the induction of tumor pyroptosis is also considered a potential cancer treatment strategy. Studies have shown that DFNA5 (nonsyndromic hearing impairment protein 5)/GSDME (Gasdermin-E) mRNA methylation results in lower expression levels of DFNA5/GSDME in most tumor cells than in normal cells, making it difficult to activate the pyroptosis in most tumor cells. During the treatment of malignant tumors, appropriate chemotherapeutic drugs can be selected according to the expression levels of DFNA5/GSDME, which can be upregulated in tumor cells, thereby increasing the sensitivity to chemotherapeutic drugs and reducing drug resistance. Therefore, induced pyroptosis may play a predominant role in the treatment of cancer. Here, we review the latest research on the anti- and protumor effects of pyroptosis and its potential applications in cancer treatment. Facts 1. Pyroptosis, a lytic, inflammatory type of regulated cell death that requires membrane-damaging gasdermin proteins, characterized by the swelling and lysis of cells, and release of many proinflammatory factors. 2. The inflammasome, caspase and gasdermin family are play key roles in pyroptosis. 3. Pyroptosis, its associated signaling pathways and the release of various inflammatory mediators are closely related to the tumorigenesis and drug resistance of tumors. 4. Triggering tumor (especially apoptosis resistance) pyroptosis holds great therapeutic potential for cancer treatment. Open questions 1. Does pyroptosis play differential roles in normal and tumor tissues? 2. What are the key signals that initiate pyroptosis? 3. What are the key signaling pathways impacted by pyroptosis in tumors? 4. How can pyroptosis be manipulated to drive tumor fate? Introduction Correspondence: Xiaojing Xia () 1 College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China 2 College of Agriculture and Forestry Science, Linyi University, Linyi, China Full list of author information is available at the end of the article. Edited by G. Raschellà The dynamic balance between cell proliferation, differentiation and death maintains ontogeny, homeostasis and pathological processes in multicellular organisms. Cell death are mainly divided into two categories, necrosis and programmed cell death (PCD). Apoptosis is a type of PCD © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Xia et al. Cell Death and Disease (2019)10:650 involving the automatic self-destruction of cells controlled by genes, the cell membrane remains intact, and generally not inducing inflammation. Necrosis is a passive type of cell death caused by pathological stimuli. The cell membrane permeability of necrotic cells increases, causing the cells to swell and eventually breakdown to release the cellular contents, leading to inflammatory reaction1. Pyroptosis is a new procedural and inflammatory death discovered after apoptosis and necrosis. Similar to apoptosis, pyroptotic cells undergo nuclear condensation and chromatin DNA fragmentation, and TUNEL staining is positive2,3. Similar to necrosis, during pyroptosis, the formation of the pores disrupts the balance of ion gradients on both sides of the cell membrane, leading to water inflow, cell swelling, cell membrane rupture, and the release of proinflammatory mediators, including IL1β, IL-18, ATP, and HMGB14, which induce inflammatory responses, thus pyroptosis is also known as inflammatory “necrosis”5,6. A close relationship between pyroptosis and various human diseases, especially malignant tumors. Pyroptosis may play a dual role in the pathogenesis of tumors. On one hand, the multiple signaling pathways and inflammatory mediators released during pyroptosis are closely related to the tumorigenesis as well as to their drug resistance to chemotherapeutic drugs7–9. On the other hand, as a type of death, pyroptosis can inhibit the occurrence and development of tumors7,10. The role of pyroptosis in tumor has become increasingly prominent as research has advanced. This review will summarize and discuss the potential effects of pyroptosis on cancer and the role of pyroptosis in anticancer therapy. Discovery of the cell pyroptosis phenomenon The term pyroptosis combines the Greek roots ‘pyro’ and ‘ptosis’, which mean fever and falling, respectively, to define a newly discovered inflammatory PCD11. As early as 1990s, scientists discovered that Shigella flexneri or Salmonella infection of mouse macrophages or human monocytes cause cell death12,13. In 1997, Arturo Zychlinsky found that Shigella dysenteriae could activate caspase-1 in host cells14. In 1999, the Arturo Zychlinsky laboratory found that knocking out caspase-1 could block the cell death caused by Salmonella15. In 2001, the laboratories of Lawrence H. Boise and Brad Cookson gradually elucidated that the macrophage death caused by bacterial infection was a death mode completely different from apoptosis and named it caspase-1-dependent programmed necrosis11,16. But until recently, a new gasdermin-D (GSDMD) (...truncated)