Necroptosis is a necrotic form of programmed cell death with potent immunogenicity that is involved in complex interactions with other types of cell death such as autophagy and apoptosis. There is growing evidence that necroptosis is involved in the regulation of various normal physiological processes, especially during the development of organisms. In addition, deregulated signaling pathways involved in the control of necroptosis are thought to underlie many human diseases, such as viral or bacterial infections, ischemic-reperfusion injury, neurodegenerative diseases, or malignancies. Among the key molecules participating in the necroptotic process are the RIPK1 and RIPK3 proteins, forming the necrosome, and the pseudokinase MLKL, which is its main effector. RIPK1 is constitutively present in both the nucleus and cytoplasm, while RIPK3 and MLKL perform continuous shuttling transport between these cell structures. Experimental pharmacological blocking of the transport mechanism leads to the impossibility of necrosome formation and thus prevention of cell death is achieved.
Suppression of cell death is a hallmark of malignant tumors. While the mechanism by which tumor cells avoid apoptosis has been well studied, information on how necroptosis is controlled by oncogenic signals in cancer cells is scarce. Many types of malignant cells have defense mechanisms against necroptotic processes by developing systems that can suppress the components involved in necroptosis. Pharmaceutical influence on the formation of the necrosome would make it possible to inhibit carcinogenesis by potentiating necroptosis and neutralizing the antinecroptotic mechanisms that a number of malignant tumors have evolutionarily acquired. In-depth study of this process can both reveal markers of important prognostic value in oncology and can identify cellular proteins as molecular targets in personalized medicine.
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