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Review
. 2019 May 23;18(1):100.
doi: 10.1186/s12943-019-1029-8.

The role of necroptosis in cancer biology and therapy

Yitao Gong  1   2   3   4 , Zhiyao Fan  1   2   3   4 , Guopei Luo  1   2   3   4 , Chao Yang  1   2   3   4 , Qiuyi Huang  1   2   3   4 , Kun Fan  1   2   3   4 , He Cheng  1   2   3   4 , Kaizhou Jin  1   2   3   4 , Quanxing Ni  1   2   3   4 , Xianjun Yu  5   6   7   8 , Chen Liu  9   10   11   12
Affiliations
Review

The role of necroptosis in cancer biology and therapy

Yitao Gong et al. Mol Cancer. .

Abstract

Apoptosis resistance is to a large extent a major obstacle leading to chemotherapy failure during cancer treatment. Bypassing the apoptotic pathway to induce cancer cell death is considered to be a promising approach to overcoming this problem. Necroptosis is a regulated necrotic cell death modality in a caspase-independent fashion and is mainly mediated by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis resistance and may trigger and amplify antitumor immunity in cancer therapy.The role of necroptosis in cancer is complicated. The expression of key regulators of the necroptotic pathway is generally downregulated in cancer cells, suggesting that cancer cells may also evade necroptosis to survive; however, in certain types of cancer, the expression level of key mediators is elevated. Necroptosis can elicit strong adaptive immune responses that may defend against tumor progression; however, the recruited inflammatory response may also promote tumorigenesis and cancer metastasis, and necroptosis may generate an immunosuppressive tumor microenvironment. Necroptosis also reportedly promotes oncogenesis and cancer metastasis despite evidence demonstrating its antimetastatic role in cancer. In addition, necroptotic microenvironments can direct lineage commitment to determine cancer subtype development in liver cancer. A plethora of compounds and drugs targeting necroptosis exhibit potential antitumor efficacy, but their clinical feasibility must be validated.Better knowledge of the necroptotic pathway mechanism and its physiological and pathological functions is urgently required to solve the remaining mysteries surrounding the role of necroptosis in cancer. In this review, we briefly introduce the molecular mechanism and characteristics of necroptosis, the interplay between necroptosis and other cell death mechanisms, crosstalk of necroptosis and metabolic signaling and detection methods. We also summarize the intricate role of necroptosis in tumor progression, cancer metastasis, prognosis of cancer patients, cancer immunity regulation, cancer subtype determination and cancer therapeutics.

Keywords: Apoptosis; Autophagy; Immunosuppression; Metastasis; Mixed lineage kinase domain-like pseudokinase (MLKL); Necroptosis; Receptor-interacting protein kinase (RIPK); Therapeutics.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
TNF necroptosis signaling mechanism
Fig. 2
Fig. 2
Role of necroptosis in cancer immunity
See this image and copyright information in PMC

References

    1. Hanahan D, Weinberg RA. Hallmarks of Cancer: the next generation. Cell. 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013. - DOI - PubMed
    1. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002;108(2):153–164. doi: 10.1016/S0092-8674(02)00625-6. - DOI - PubMed
    1. Linkermann A, Green DR. Necroptosis. N Engl J Med. 2014;370(5):455–465. doi: 10.1056/NEJMra1310050. - DOI - PMC - PubMed
    1. Christofferson DE, Yuan J. Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol. 2010;22(2):263–268. doi: 10.1016/j.ceb.2009.12.003. - DOI - PMC - PubMed
    1. Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4:313. doi: 10.1038/nchembio.83. - DOI - PMC - PubMed

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