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DNA Damage and Cellular Stress Responses

Nuclear Factor-B p65 Inhibits Mitogen-Activated Protein Kinase Signaling Pathway in Radioresistant Breast Cancer Cells

¹ Division of Molecular Radiobiology, Purdue University School of Health Sciences, West Lafayette, Indiana and ² Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

Requests for reprints: Jian Jian Li, Division of Molecular Radiobiology, Purdue University School of Health Sciences, Room 1279, Civil Engineering Building, 550 Stadium Mall Drive, West Lafayette, IN 47907. Phone: 765-496-6792; Fax: 765-496-1377. Email: jjli{at}purdue.edu

The molecular mechanism by which tumor cells increase their resistance to therapeutic radiation remains to be elucidated. We have previously reported that activation of nuclear factor-B (NF-B) is causally associated with the enhanced cell survival of MCF+FIR cells derived from breast cancer MCF-7 cells after chronic exposure to fractionated ionizing radiation. The aim of the present study was to reveal the context of NF-B pathways in the adaptive radioresistance. Using cell lines isolated from MCF+FIR populations, we found that the elevated NF-B activity was correlated with enhanced clonogenic survival, and increased NF-B subunit p65 levels were associated with a decrease in phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK in all radioresistant MCF+FIR cell lines. Further irradiation with 30 fractions of radiation also inhibited MEK/ERK phosphorylation in paired cell lines of MCF+FIR and parental MCF-7 cells. Activation of ataxia-telangiectasia mutated (ATM) protein, a sensor to radiation-induced DNA damage, was elevated with increased interaction with NF-B subunits p65 and p50. The interaction between p65 and MEK was also enhanced in the presence of activated ATM. In contrast, both interaction and nuclear translocation of p65/ERK were reduced. Inhibition of NF-B by overexpression of mutant IB increased ERK phosphorylation. In addition, MEK/ERK inhibitor (PD98059) reduced the interaction between p65 and ERK. Taken together, these results suggest that NF-B inhibits ERK activation to enhance cell survival during the development of tumor adaptive radioresistance. (Mol Cancer Res 2006;4(12):945–55)

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