Emerging mechanisms of pyroptosis and its therapeutic strategy in cancer

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Abstract

Pyroptosis, a type of inflammatory programmed cell death, is triggered by caspase cleavage of gasdermin family proteins. Based on accumulating evidence, pyroptosis is closely associated with tumour development, but the molecular mechanism underlying pyroptosis activation and the signalling pathways regulated by pyroptosis remain unclear. In this review, we first briefly introduce the definition, morphological characteristics, and activation pathways of pyroptosis and the effect of pyroptosis on anticancer immunity. Then we review recent progress concerning the complex role of pyroptosis in various tumours. Importantly, we summarise various FDA-approved chemotherapy drugs or natural compounds that exerted antitumor properties by inducing pyroptosis of cancer cells. Moreover, we also focus on the current application of nanotechnology-induced pyroptosis in tumour therapy. In addition, some unsolved problems and potential future research directions are also raised.

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Most cited references 149

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Cancer statistics, 2019

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2019)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.

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Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Lorenzo Galluzzi, Ilio Vitale, Stuart A. Aaronson … (2018)

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

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Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.

Jianjin Shi, Yue Zhao, Kun Wang … (2015)

Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1β release was also diminished in Gsdmd(-/-) cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.

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Author and article information

Contributors

Ting Liu:

ORCID: http://orcid.org/0000-0001-8178-6532

liuting818@126.com

Yongheng Chen:

ORCID: http://orcid.org/0000-0001-8139-6892

yonghenc@163.com

Journal

Journal ID (nlm-ta): Cell Death Discov

Journal ID (iso-abbrev): Cell Death Discov

Title: Cell Death Discovery

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2058-7716

Publication date (Electronic): 27 July 2022

Publication date PMC-release: 27 July 2022

Publication date Collection: 2022

Volume: 8

Electronic Location Identifier: 338

Affiliations

[1 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Thoracic Surgery, Xiangya Hospital, , Central South University, ; Changsha, 410008 People’s Republic of China

[2 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, , Central South University, ; 410008 Changsha, Hunan China

[3 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Gastroenterology, Xiangya Hospital, , Central South University, ; Changsha, China

[4 ]GRID grid.18763.3b, ISNI 0000000092721542, School of Biological and Medical Physics, , Moscow Institute of Physics and Technology, ; 141700 Dolgoprudny, Moscow Region Russia

[5 ]GRID grid.470117.4, Institute of Cell Biophysics, , Russian Academy of Sciences, ; 142290 Pushchino, Russia

[6 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Shanghai Institute of Precision Medicine, Ninth People’s Hospital, , Shanghai Jiao Tong University School of Medicine, ; 200125 Shanghai, China

[7 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, National Clinical Research Center for Geriatric Disorders, XiangYa Hospital, , Central South University, ; 410008 Changsha, China

Author information

Ting Liu http://orcid.org/0000-0001-8178-6532

Yongheng Chen http://orcid.org/0000-0001-8139-6892

Article

Publisher ID: 1101

DOI: 10.1038/s41420-022-01101-6

PMC ID: 9329358

PubMed ID: 35896522

SO-VID: c5114d53-aa3d-43ce-9eaa-70dbf3086677

License:

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/.

History

Date received : 14 June 2022

Date revision received : 20 June 2022

Date accepted : 23 June 2022

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81570537

Award ID: 81974074

Award ID: 81902858

Award ID: 82070632

Award Recipient : Ye Zhang Ting Liu Yongheng Chen

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Keywords: cancer,immunology

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Keywords: cancer, immunology

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Emerging mechanisms of pyroptosis and its therapeutic strategy in cancer

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Cancer Metabolism

Most cited references 149

Cancer statistics, 2019

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.

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Cited by 24

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