ATM-NF-kappaB connection as a target for tumor radiosensitization

Curr Cancer Drug Targets. 2007 Jun;7(4):335-42. doi: 10.2174/156800907780809769.

Abstract

Ionizing radiation (IR) plays a key role in both areas of carcinogenesis and anticancer radiotherapy. The ATM (ataxia-telangiectasia mutated) protein, a sensor to IR and other DNA-damaging agents, activates a wide variety of effectors involved in multiple signaling pathways, cell cycle checkpoints, DNA repair and apoptosis. Accumulated evidence also indicates that the transcription factor NF-kappaB (nuclear factor-kappaB) plays a critical role in cellular protection against a variety of genotoxic agents including IR, and inhibition of NF-kappaB leads to radiosensitization in radioresistant cancer cells. NF-kappaB was found to be defective in cells from patients with A-T (ataxia-telangiectasia) who are highly sensitive to DNA damage induced by IR and UV lights. Cells derived from A-T individuals are hypersensitive to killing by IR. Both ATM and NF-kappaB deficiencies result in increased sensitivity to DNA double strand breaks. Therefore, identification of the molecular linkage between the kinase ATM and NF-kappaB signaling in tumor response to therapeutic IR will lead to a better understanding of cellular response to IR, and will promise novel molecular targets for therapy-associated tumor resistance. This review article focuses on recent findings related to the relationship between ATM and NF-kappaB in response to IR. Also, the association of ATM with the NF-kappaB subunit p65 in adaptive radiation response, recently observed in our lab, is also discussed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology*
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Humans
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • Neoplasms / metabolism
  • Neoplasms / physiopathology
  • Neoplasms / radiotherapy*
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Radiation Tolerance*
  • Signal Transduction
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / physiology*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • NF-kappa B
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases