Radiation-induced Cell Death and Its Mechanisms

Abstract

With rapid technical advances, ionizing radiation has been put into wider application in ordinary living, with the worst cytological effect on the human body being cell death. Moreover, according to the Nomenclature Committee on Cell Death, the method of radiation-induced cell death, usually classified as interphase and proliferative death, undergoes more detailed classifications oriented by its molecular mechanism. Elaborating its mode and molecular mechanism is crucial for the protection and treatment of radiation injury, as well as the radiotherapy and recovery of tumors. Varying with the changes of the radiation dose and the environment, the diverse targets and pathways of ionizing radiation result in various cell deaths. This review focuses on classifications of radiation-induced cell death and its molecular mechanism. We also examine the main characteristics of ionizing radiation-induced cell death. The modes of radiation-induced cell death can be classified as apoptosis, necrosis, autophagy-dependent cell death, pyroptosis, ferroptosis, immunogenic cell death, and non-lethal processes. Once the dose is high enough, radiation effects mostly appear as destructiveness ("destructiveness" is used to describe a situation in which cells do not have the opportunity to undergo a routine death process, in which case high-dose radiation works like a physical attack). This breaks up or even shatters cells, making it difficult to find responses of the cell itself. Due to diversities concerning cell phenotypes, phases of cell cycle, radiation dose, and even cellular subregions, various methods of cell death occur, which are difficult to identify and classify. Additionally, the existence of common initial activation and signaling molecules among all kinds of cell deaths, as well as sophisticated crossways in cellular molecules, makes it more laborious to distinguish and classify various cell deaths.

Fig. 1

Signaling pathways involved in radiation-induced apoptosis. After being induced by radiation, the initiation of apoptosis is mainly activated by two different pathways, intrinsic and extrinsic, both of which ultimately complete apoptosis by activating the execution pathway. Additionally, ionizing radiation can promote apoptosis in other two ways, P53 and SAPK/JNK pathways.

Fig. 2

Signaling pathways involved in radiation-induced necroptosis. According to the key executive molecules, cell necrosis can be divided into "MPT (mitochondrial permeability transition)-driven necrosis," "necroptosis," and "Parthanatos."

Fig. 3

Signaling pathways involved in radiation-induced autophagy-dependent cell death. The initiation of classical autophagy pathway is mainly accomplished by the interaction of mammalian target of rapamycin complex 1(mTORC1) and ULK 1 (Atg 1) complex. Moreover, there is an atypical cell autophagy called Mitochondrial autophagy (Mitophagy), whose pathway is mainly dependent or independent of the interaction of PINK1 (a mitochondrial-specific kinase), PARKIN and E3 ubiquitin ligase.

Fig. 4

Signaling pathways involved in radiation-induced pyroptosis and ferroptosis. Various pathways induce ferroptosis directly or indirectly by affecting the activity of glutathione peroxidase(GPXs). These pathways include system Xc-, P53, GPX4, transportation of voltage-dependent anion channels/VDACs, methionine sulfur transfer pathway, heme oxygenase 1/HO-1, and the internal iron source of transferrin.