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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 the DNA-damage response in normal tissues and in tumours. So, p53 inhibition can reduce normal tissue damage and sensitize tumour cells for treatment.

Abstract

Ionizing radiation (IR) has proven to be a powerful medical treatment in the fight against cancer. Rational and effective use of its killing power depends on understanding IR-mediated responses at the molecular, cellular and tissue levels. Tumour cells frequently acquire defects in the molecular regulatory mechanisms of the response to IR, which sensitizes them to radiation therapy. One of the key molecules involved in a cell's response to IR is p53. Understanding these mechanisms indicates new rational approaches to improving cancer treatment by IR.

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Figure 1: Critical decision points of an IR-treated cell.
Figure 2: Factors that might determine the outcome of p53 activation by IR.
Figure 3: Cell-type specificity of p53-mediated response to IR and its alteration in p53-deficient cells.

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Acknowledgements

We thank all members of our laboratory and collaborators for their impact in formation of the authors' view on the problem of radiation response in vivo. The authors' experimental research is supported by grants from the National Cancer Institute and Quark Biotech, Inc. (to A.V.G.).

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Correspondence to Andrei V. Gudkov.

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DATABASES

LocusLink

APAF1

Atm

ATM

Bax

Bcl2

BCL2

BCL-XL

CDKN2A

Chk2

CHK2

cyclin D1

E2F

Fas

FAS

Hras

IL-1

IL-6

IL-12

Killer

MDM2

Myc

p53

Pig8

RB

SCF

TGF-β

TGF-β2

TNF

TRAIL

Glossary

IONIZING RADIATION

(IR). Corpuscular or electromagnetic radiation that is capable of producing ions, directly or indirectly, in its passage through matter. The absorbed dose of ionizing radiation is measured as the gray (Gy, 1 joule of energy absorbed by 1 kilogram of material).

GAMMA-RAYS AND X-RAYS

The distinction between gamma-rays and X-rays lies in their origin: gamma-rays originate from excited and unstable nuclei, whereas X-rays are produced by electron energy transitions within the atom or through the deceleration of high-kinetic energy electrons.

RADIATION RESISTANCE (SENSITIVITY)

A relative term, the exact meaning of which depends on the subject and context. At the level of the organism, it is related to the ability to survive after exposure to ionizing radiation. At the tissue level, it describes the ability of the tissue or organ to maintain structural and functional integrity after irradiation. At the cellular level, it might either reflect the cell's ability to continue normal proliferation (form colonies in colony assays) or to retain viability (determined by cell-viability assays).

GENOTOXIC STRESS

Different types of DNA damage that are recognized by stress-response sensor mechanisms and activate DNA repair, including double-stranded and single-stranded DNA breaks and covalent modifications of DNA.

CELL-CYCLE CHECKPOINTS

A series of control mechanisms that induce growth arrest and act at several specific stages of the cell cycle. These prevent cells from entering into a new phase until they have successfully completed the previous one.

MITOTIC CATASTROPHE

A series of pathological events that occur after aberrant mitosis and usually result in cell death. Such a mitosis does not produce proper chromosome segregation and cell division, but leads to the formation of large non-viable cells with several nuclei, containing fractions of broken chromosomes. It can be followed by apoptosis.

CLONOGENIC POTENTIAL

The ability of the cell to propagate and to serve as a progenitor of a clone. Estimated by clonogenic or colony assays in vivo and in vitro.

ATAXIA TELANGIECTASIA

Ataxia telangiectasia (AT) is an inherited syndrome that is characterized by cerebellar ataxia, telangiectases (dilated small blood vessels that appear in specific locations), immunodeficiency, radiosensitivity and predisposition to lymphatic leukaemias and other malignancies. It is associated with defects in the ATM gene, which encodes a 370-kDa protein — a member of the phosphatidylinositol 3-kinases superfamily — that mediates activation of DNA repair and p53 pathways.

REACTIVE OXYGEN SPECIES

(ROS). Highly reactive chemical radicals that are generated as products of oxygen degradation.

BCL2

BCL2 is an anti-apoptotic protein that is a member of a large family of proteins, consisting of anti-apoptotic and pro-apoptotic members. These proteins regulate the release of cytochrome c from mitochondria, leading to activation of the proteolytic caspase cascade and apoptosis.

MYELOABLATION

Depletion of bone-marrow haematopoietic cells, resulting in subsequent reduction of peripheral-blood cell counts.

BYSTANDER EFFECT

Indirect cytotoxicity of radiation or drugs to unaffected healthy cells that results from changes in tissue microenvironment caused by treatment-induced damage to neighbouring cells.

OLIGODENDROCYTES

The non-neural cells of ectodermal origin that form part of the adventitial structure of the central nervous system.

FIBROSIS

A common pathological consequence of tissue irradiation that develops a long time after treatment (months and years in radiation-treated cancer patients). It is characterized by abnormal proliferation of different cell components within tissue and results in substitution of epithelia for connective tissue.

CYTOKINES

Hormone-like proteins that are produced by stimulated cells and serve as intercellular messengers. Cytokines are pleiotropic: they act on multiple cells via high-affinity membrane receptors. Signalling by the cytokine–receptor complex leads to stimulation of a diverse range of cell functions, including production of cytokines, growth and proliferation, differentiation, motility, apoptosis and growth inhibition.

HYPOTHALAMIC SUPRACHIASMATIC NUCLEUS

The part of the brain that directs behavioural and physiological oscillations in the entire mammalian organism.

REPLICATIVE SENESCENCE

Permanent growth arrest that cells undergo in culture (and presumably in tissues) after their telomeres become critically short as a result of multiple cell divisions.

THERAPEUTIC INDEX

The ratio between therapeutic effect and the damage caused by treatment.

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Gudkov, A., Komarova, E. The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer 3, 117–129 (2003). https://doi.org/10.1038/nrc992

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