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RIPK3 signaling and its role in the pathogenesis of cancers

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Abstract

RIPK3 (receptor-interacting protein kinase 3) is a serine/threonine-protein kinase. As a key component of necrosomes, RIPK3 is an essential mediator of inflammatory factors (such as TNFα-tumor necrosis factor α) and infection-induced necroptosis, a programmed necrosis. In addition, RIPK3 signaling is also involved in the regulation of apoptosis, cytokine/chemokine production, mitochondrial metabolism, autophagy, and cell proliferation by interacting with and/or phosphorylating the critical regulators of the corresponding signaling pathways. Similar to apoptosis, RIPK3-signaling-mediated necroptosis is inactivated in most types of cancers, suggesting RIPK3 might play a critical suppressive role in the pathogenesis of cancers. However, in some inflammatory types of cancers, such as pancreatic cancers and colorectal cancers, RIPK3 signaling might promote cancer development by stimulating proliferation signaling in tumor cells and inducing an immunosuppressive response in the tumor environment. In this review, we summarize recent research progress in the regulators of RIPK3 signaling, and discuss the function of this pathway in the regulation of mixed lineage kinase domain-like (MLKL)-mediated necroptosis and MLKL-independent cellular behaviors. In addition, we deliberate the potential roles of RIPK3 signaling in the pathogenesis of different types of cancers and discuss the potential strategies for targeting this pathway in cancer therapy.

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Funding

This work was supported by NIH Grants R01 HL133560-01 and R01 CA223194-01 through Loyola University Chicago, as well as Loyola program development funds to Jiwang Zhang.

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  1. Shanhui Liu and Kanak Joshi contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, 60153, USA

    Shanhui Liu, Kanak Joshi, Mitchell F. Denning & Jiwang Zhang

  2. Department of Pathology and Department of Radiation Oncology, Loyola University Medical Center, Maywood, IL, 60153, USA

    Jiwang Zhang

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  1. Shanhui Liu
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SL drafted the first version of this review. All authors contributed to the writing of this manuscript. All authors read and approved the final manuscript.

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Liu, S., Joshi, K., Denning, M.F. et al. RIPK3 signaling and its role in the pathogenesis of cancers. Cell. Mol. Life Sci. 78, 7199–7217 (2021). https://doi.org/10.1007/s00018-021-03947-y

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