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Radiother Oncol. 2009 Sep;92(3):379-82. doi: 10.1016/j.radonc.2009.06.003. Epub 2009 Jun 25.

Radiation-induced lipid peroxidation activates src kinase and triggers nuclear EGFR transport.

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  • 1Department of Radiation Oncology, Eberhard-Karls-University, Röntgenweg, Germany. klaus.dittmann@uni-tuebingen.de

Abstract

PURPOSE:

Elucidation of the molecular mechanism of radiation-induced activation of src kinase, which initiates EGFR internalization and nuclear transport.

MATERIAL AND METHODS:

Radiation-induced src activation was investigated in the bronchial carcinoma cell line A549. Proteins were Western blotted and quantified by the help of specific antibodies. Residual DNA-damage was quantified with gammaH(2)AX-foci analysis. Radiation-induced lipid peroxidation was prevented by acetyl-cysteine.

RESULTS:

The radiation-induced src activation and EGFR stabilization could be mimicked by addition of hydroxy-nonenal (HNE), one of the major lipid peroxidation products. Radiation-generated HNE is bound to EGFR and src and correlated with complex formation between both following radiation. Treatment with HNE activated src and stimulated radiation-associated EGFR and caveolin 1 phosphorylations resulting in increased nuclear transport of EGFR. Consequently, radiation-induced phosphorylation and activation of DNA-PK were increased. This phosphorylation was associated with improved removal of residual damage 24h after irradiation. Inhibition of radiation-induced HNE generation by acetyl-cysteine blocked radiation-induced src activation and EGFR phosphorylation.

CONCLUSIONS:

HNE generated in response to radiation exposure activates src kinase and is involved in regulation of radiation-stimulated DNA-repair processes.

PMID:
19560222
DOI:
10.1016/j.radonc.2009.06.003
[PubMed - indexed for MEDLINE]
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