The role of p53 in determining sensitivity to radiotherapy

Key Points Ionizing radiation (IR) has proved to be a powerful tool in the treatment of cancer. However, it also has serious side effects for normal tissues. The overall sensitivity of a mammalian organism to IR is determined by the pathological alterations that occur in a few sensitive tissues. Organisms that survive acute toxicity of radiation can suffer from long-term remote consequences, including radiation-induced carcinogenesis and fibrosis, which develop in exposed organs (such as the kidneys, liver or lungs) months and years after irradiation. Cellular DNA is the main target of IR; it causes DNA damage (genotoxic stress) by direct and indirect (free-radical-based) mechanisms. All organisms maintain a DNA-repair system that is capable of effective recovery of radiation-damaged DNA; errors in the DNA-repair process might lead to mutations and an increased risk of cancer development. At the molecular level, radiation-induced damage results in activation of DNA repair, coupled with arrest at cell-cycle checkpoints, which allows the cell to repair the damage before proceeding through mitosis. This mechanism is conserved in all eukaryotes. Multicellular organisms have acquired additional response mechanisms to genotoxic stress, which involve activation of the transcription factor p53. p53 can induce growth arrest or apoptosis, and these responses maintain genomic stability. Failure of this system results in cancer development and genomic instability. The ways in which cells respond to IR are tissue specific and vary greatly during embryogenesis. Cells with a high proliferative capacity tend to apoptose, whereas fibroblasts — the structural component of tissues — tend to growth arrest. Tumours are generally highly sensitive to gamma-radiation — because of loss of negative growth regulation and genomic stability — and are treated with many local doses to reduce damage to normal tissues. Apoptosis has a relatively modest role in the tumour response to radiation; most tumours lose the ability to apoptose. The antitumour effect of radiation is realized through mitotic catastrophe or in senescence-like irreversible growth arrest. Radiation sensitivity involves both intrinsic mechanisms and bystander effects, in which the failure of a certain cell type within the complex mix of tumour and normal cells leads to a chain of reactions that results in tissue failure. Facilitation of radiation therapy outcome can be achieved by modulating the molecular mechanisms of