Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, 60153, USA.
Department of Pathology and Department of Radiation Oncology, Loyola University Medical Center, Maywood, IL, 60153, USA.
Cell Mol Life Sci. 2021 Dec;78(23):7199-7217. doi: 10.1007/s00018-021-03947-y. Epub 2021 Oct 15.
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.
RIPK3（受体相互作用蛋白激酶 3）是一种丝氨酸/苏氨酸蛋白激酶。作为坏死小体的关键组成部分，RIPK3 是炎症因子（如 TNFα-肿瘤坏死因子 α）和感染诱导的程序性坏死（坏死细胞死亡）的必需介质。此外，RIPK3 信号还通过与相应信号通路的关键调节因子相互作用和/或磷酸化来调节细胞凋亡、细胞因子/趋化因子产生、线粒体代谢、自噬和细胞增殖。与细胞凋亡相似，RIPK3 信号介导的坏死细胞死亡在大多数类型的癌症中失活，表明 RIPK3 可能在癌症的发病机制中发挥关键抑制作用。然而，在某些炎症类型的癌症中，如胰腺癌和结直肠癌，RIPK3 信号可能通过刺激肿瘤细胞中的增殖信号和诱导肿瘤微环境中的免疫抑制反应来促进癌症的发展。在这篇综述中，我们总结了 RIPK3 信号调节因子的最新研究进展，并讨论了该通路在混合谱系激酶结构域样（MLKL）介导的坏死和 MLKL 非依赖性细胞行为调节中的功能。此外，我们还讨论了 RIPK3 信号在不同类型癌症发病机制中的潜在作用，并讨论了针对该通路在癌症治疗中的潜在策略。
