Journal
CANCER RESEARCH
Volume 67, Issue 7, Pages 3220-3228Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-06-2728
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- PHS HHS [R01 101990] Funding Source: Medline
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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 gamma-rays. To elucidate the molecular pathways of LDIR-induced adaptive radioresistance, the transcription factor nuclear factor-kappa B (NF-kappa B) and a group of NF-kappa B-related proteins [i.e., p65, manganese superoxide dismutase (MnSOD), phosphorylated extracellular signal-regulated kinase, cyclin B1, and 14-3-3 zeta] were identified to be activated as early as 15 min after LDIR. Further analysis revealed that a substantial amount of both 14-3-3 zeta and cyclin B I accumulated in the cytoplasm at 4 to 8 h when cell survival was enhanced. The nuclear 14-3-3 zeta and cyclin B1 were reduced and increased at 4 and 24 h, respectively, after LDIR. Using YFP-fusion gene expression vectors, interaction between 14-3-3 zeta and cyclin B1 was visualized in living cells, and LDIR enhanced the nuclear translocation of the 14-3-3 zeta/cyclin B1 complex. Treatment of JB6P+ cells with the NF-kappa B inhibitor IMD-0354 suppressed LDIR-induced expression of MnSOD, 14-3-3 zeta, 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-kappa B, MnSOD, 14-3-3 zeta, and cyclin B1 contribute to LDIR-induced adaptive radioresistance in mouse skin epithelial cells.
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