Cellular Stress Responses in Radiotherapy

Abstract

Radiotherapy is one of the major cancer treatment strategies. Exposure to penetrating radiation causes cellular stress, directly or indirectly, due to the generation of reactive oxygen species, DNA damage, and subcellular organelle damage and autophagy. These radiation-induced damage responses cooperatively contribute to cancer cell death, but paradoxically, radiotherapy also causes the activation of damage-repair and survival signaling to alleviate radiation-induced cytotoxic effects in a small percentage of cancer cells, and these activations are responsible for tumor radio-resistance. The present study describes the molecular mechanisms responsible for radiation-induced cellular stress response and radioresistance, and the therapeutic approaches used to overcome radioresistance.

Keywords: DNA damage response; ER stress; Radiation response; autophagy; lipid peroxidation; mitochondrial damage; radioresistance; reactive oxygen species.

Figure 1

Radiation-induced reactive oxygen species (ROS) response associated with p53 signaling. Irradiation increases intracellular ROS levels facilitated by radiation-mediated mitochondrial damage. In the presence of elevated ROS levels, p53 may importantly ameliorate radiation-induced oxidative stress.

Figure 2

Radiation-induced double-strand breaks (DSB) response. When DSBs are induced by irradiation, DNA damage-sensing and repair proteins such as ATM, ATR, DNA-PK, H2AX, MDC1, Chk1, and Chk2 are activated. Subsequently, p53 is activated and induces cell cycle arrest for the homologous recombination (HR) or non-homologous end joining (NHEJ) pathways or induces apoptosis by upregulating proapoptotic genes.

Figure 3

Radiation-induced lipid peroxidation and ceramide signaling. Exposure of the plasma membrane to penetrating radiation leads to the production of homologous recombination (HNE), arachidonic acid-derived lipid metabolites, and ceramide. HNE is associated with the stimulation of unfolded protein response (UPR), and arachidonic acid metabolites promote cell proliferation, inflammation, and protect cells from apoptosis, and thus, contribute to tumor radioresistance. On the other hand, ceramide triggers apoptosis by activating Fas and Bak/Bax signaling and inhibiting PI3K/Akt signaling.

Figure 4

Radiation-induced mitochondrial response. Radiation induces mitochondrial damage largely via ROS generation. Excessive ROS levels and radiation-induced p53-dependent upregulations of PUMA and Bak/Bax result in mitochondrial membrane permeabilization and subsequent release of cytochrome c into cytosol, and thus, promote intrinsic apoptotic signaling.

Figure 5

Radiation-induced ER stress response. Radiation can induce ER stress directly or indirectly by generating ROS. Under radiation-induced ER stress, specific signaling by PERK, ATF6, and IRE1 may be activated, and augment the upregulations of UPR-related genes to improve chaperone activity and induce autophagy to recover and recycle misfolded proteins.