The role of necroptosis in cancer biology and therapy

• Published in: Molecular cancer Vol. 18; no. 1; pp. 100 - 17
• Main Authors: Gong, Yitao, Fan, Zhiyao, Luo, Guopei, Yang, Chao, Huang, Qiuyi, Fan, Kun, Cheng, He, Jin, Kaizhou, Ni, Quanxing, Yu, Xianjun, Liu, Chen
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 23.05.2019; BioMed Central; BMC
• Subjects: Adaptive immunity; Antitumor activity; Apoptosis; Autophagy; Biology; Cancer; Cancer therapies; Care and treatment; Caspase; Cell death; Chemotherapy; Disease Progression; Drug delivery; Drug development; Drug resistance; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Immune response; Immunosuppressive agents; Inflammation; Kinases; Ligands; Liver cancer; MAP kinase; Metastases; Metastasis; Microenvironments; Mixed lineage kinase domain-like pseudokinase (MLKL); Necroptosis; Neoplasms - immunology; Neoplasms - metabolism; Protein Kinases - metabolism; Proteins; Receptor-interacting protein kinase (RIPK); Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Review; T cell receptors; Tumor Microenvironment; Tumor necrosis factor-TNF; Tumorigenesis; Immunosuppression; Receptor-interacting protein kinase (RIPK); Mixed lineage kinase domain-like pseudokinase (MLKL); Necroptosis; Therapeutics; Metastasis; Autophagy; Apoptosis
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-019-1029-8

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.