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

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.

Fig. 1

Cell extracts of MCF-7, MCF+FIR C6, and ATM-deficient GM05849 fibroblasts (as a negative control) were immunoprecipitated with an anti-ATM antibody and then blotted with p65, p50 or ATM antibody. For another negative control (Neg. control), immunoprecipitation (IP) and immunoblotting (IB) were performed without cell extracts [113].

Scheme 1

Schematic presentation of the ATM-NF-κB connection in adaptive radioresistance. In chronic response (cells with pre-irradiation), ATM interacts directly with NF-κB subunits p65 and p50, resulting in the induction of both activity and expression of NF-κB. This event causes the interaction of p65 with MEK/ERK, resulting MEK/ERK inhibition. Therefore, ATM-mediated negative regulation of NF-κB on MEK/ERK pathway may cause increased cell survival under the genotoxic conditions of a long-term therapeutic irradiation.

Scheme 2

ATM-NF-κB-regulated signaling network causing the adaptive resistance to IR in normal human skin epithelial HK18 cells. Low level radiation induces ATM-NF-κB p65 interaction through NF-κB activation by an ATM-dependent fashion (ATM/unknown kinase/MEK/ERK pathway). These events result in up-regulation of 14-3-3s and cyclins, and a reduction of 14-3-3ζ-cyclin D1 complex. Overall, these results demonstrate a novel molecular events of adaptive radioresistance involving ATM-NF-κB connection in human keratinocytes.