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6 August 2013 Mitigation of Radiation-Induced Damage by Targeting EGFR in Noncancerous Human Epithelial Cells
Sang Bum Kim, Peter Ly, Aadil Kaisani, Lu Zhang, Woodring E. Wright, Jerry W. Shay
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Abstract

Methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate (CDDO-Me) is an antioxidative, anti-inflammatory modulator, which activates the nuclear factor-erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. While CDDO-Me has radioprotective activity through Nrf2 activation in vitro and in vivo, its ability to mitigate radiation-induced damage when provided after irradiation has not been studied. Here we investigated whether CDDO-Me mitigates ionizing radiation (IR)-induced DNA damage in immortalized normal human colonic epithelial cells (HCECs) and bronchial epithelial cells (HBECs). DNA damage and clonogenic survival were assessed after treatment with CDDO-Me postirradiation. We observed that treatment with CDDO-Me within 30 min after irradiation improved both DNA damage repair and clonogenic survival independently of Nrf2. CDDO-Me activates the epidermal growth factor receptor (EGFR) related DNA repair responses. In the presence of CDDO-Me, EGFR is phosphorylated and translocates into the nucleus where it interacts with DNA-PKcs. CDDO-Me-mediated mitigation activity can be abrogated through depletion of EGFR, ectopic overexpression of mutant EGFR or inhibition of DNA-PKcs. While post-treatment of CDDO-Me protected noncancerous HCECs and HBECs against IR, cancer cells (HCT116 and MCF7) were not protected by CDDO-Me. These results suggest that targeting EGFR using CDDO-Me is a promising radiation mitigator with potential utility for first responders to nuclear accidents.

Sang Bum Kim, Peter Ly, Aadil Kaisani, Lu Zhang, Woodring E. Wright, and Jerry W. Shay "Mitigation of Radiation-Induced Damage by Targeting EGFR in Noncancerous Human Epithelial Cells," Radiation Research 180(3), 259-267, (6 August 2013). https://doi.org/10.1667/RR3371.1
Received: 26 August 2012; Accepted: 1 April 2013; Published: 6 August 2013
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