title: Mitigation of radiation-induced damage by targeting EGFR in noncancerous human epithelial cells.
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.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Sang Bum
authors.initials: SB
authors.lastname: Kim
authors.forename: Peter
authors.initials: P
authors.lastname: Ly
authors.forename: Aadil
authors.initials: A
authors.lastname: Kaisani
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Woodring E
authors.initials: WE
authors.lastname: Wright
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair; D004847:Epithelial Cells / Q000528:radiation effects; D066246:ErbB Receptors / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans
chemical_list: D066246:ErbB Receptors