Nuclear factor-κB p65 inhibits mitogen-activated protein kinase signaling pathway in radioresistant breast cancer cells

Kazi M. Ahmed, Shaozhong Dong, Ming Fan, Jian-Jian Li

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

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-κB (NF-κB) 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-κB pathways in the adaptive radioresistance. Using cell lines isolated from MCF+FIR populations, we found that the elevated NF-κB activity was correlated with enhanced clonogenic survival, and increased NF-κB 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-κB 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-κB by overexpression of mutant IκB increased ERK phosphorylation. In addition, MEK/ERK inhibitor (PD98059) reduced the interaction between p65 and ERK. Taken together, these results suggest that NF-κB inhibits ERK activation to enhance cell survival during the development of tumor adaptive radioresistance.

Original languageEnglish (US)
Pages (from-to)945-955
Number of pages11
JournalMolecular Cancer Research
Volume4
Issue number12
DOIs
StatePublished - Dec 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'Nuclear factor-κB p65 inhibits mitogen-activated protein kinase signaling pathway in radioresistant breast cancer cells'. Together they form a unique fingerprint.

  • Cite this