Nuclear factor-κB and manganese superoxide dismutase mediate adaptive radioresistance in low-dose irradiated mouse skin epithelial cells

Ming Fan, Kazi Mokim Ahmed, Mitchell C. Coleman, Douglas R. Spitz, Jian-Jian Li

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Mechanisms governing inducible resistance to ionizing radiation in untransformed epithelial cells pre-exposed to low-dose ionizing radiation (LDIR; ≤10 cGy) are not well understood. The present study provides evidence that pre-exposure to 10 cGy X-rays increases clonogenic survival of mouse skin JB6P+ epithelial cells subsequently exposed to 2 Gy doses of γ-rays. To elucidate the molecular pathways of LDIR-induced adaptive radioresistance, the transcription factor nuclear factor-κB (NF-κB) and a group of NF-κB-related proteins [i.e., p65, manganese superoxide dismutase (MnSOD), phosphorylated extracellular signal-regulated kinase, cyclin B1, and 14-3-3ζ] were identified to be activated as early as 15 min after LDIR. Further analysis revealed that a substantial amount of both 14-3-3ζ, and cyclin B1 accumulated in the cytoplasm at 4 to 8 h when cell survival was enhanced. The nuclear 14-3-3ζ, and cyclin B1 were reduced and increased at 4 and 24 h, respectively, after LDIR. Using YFP-fusion gene expression vectors, interaction between 14-3-3ζ and cyclin B1 was visualized in living cells, and LDIR enhanced the nuclear translocation of the 14-3-3ζ/cyclin B1 complex. Treatment of JB6P+ cells with the NF-κB inhibitor IMD-0354 suppressed LDIR-induced expression of MnSOD, 14-3-3ζ, and cyclin B1 and diminished the adaptive radioresistance. In addition, treatment with small interfering RNA against mouse MnSOD was shown to inhibit the development of LDIR-induced radioresistance. Together, these results show that NF-κB, MnSOD, 14-3-3ζ, and cyclin B1 contribute to LDIR-induced adaptive radioresistance in mouse skin epithelial cells.

Original languageEnglish (US)
Pages (from-to)3220-3228
Number of pages9
JournalCancer Research
Volume67
Issue number7
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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