title: Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation.
abstract: Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator for antioxidant and anti-inflammation enzymes that binds to its endogenous inhibitor protein, Kelch-like ECH (erythroid cell-derived protein with CNC homology)-associated protein 1, in the cytoplasm under normal conditions. Various endogenous or environmental oxidative stresses, such as ionizing radiation (IR), can disrupt the Nrf2-Kelch-like ECH-associated protein 1 complex. This allows Nrf2 to translocate from the cytoplasm into the nucleus to induce transcription of heme oxygenase-1 and other cytoprotective enzymes through binding to antioxidant responsive elements. However, how Nrf2 protects cells from IR-induced damage remains unclear. Here, we report that Nrf2 activation by the synthetic triterpenoids, bardoxolone methyl (BARD) and 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid-ethyl amide, protects colonic epithelial cells against IR-induced damage, in part, by enhancing signaling of the DNA damage response. Pretreatment with BARD reduced the frequency of both G1 and S/G2 chromosome aberrations and enhanced the disappearance of repairosomes (C-terminal binding protein interacting protein, Rad51, and p53 binding protein-1 foci) after IR. BARD protected cells from IR toxicity in a Nrf2-dependent manner. The p53 binding protein-1 promoter contains three antioxidant responsive elements in which Nrf2 directly binds following BARD treatment. In addition, 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid-ethyl amide provided before exposure to a lethal dose of whole-body irradiation protected WT mice from DNA damage and acute gastrointestinal toxicity, which resulted in improved overall survival. These results demonstrate that Nrf2 activation by synthetic triterpenoids is a promising candidate target to protect the gastrointestinal tract against acute IR in vitro and in vivo.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039, USA.
authors.forename: Sang Bum
authors.initials: SB
authors.lastname: Kim
authors.forename: Raj K
authors.initials: RK
authors.lastname: Pandita
authors.forename: Ugur
authors.initials: U
authors.lastname: Eskiocak
authors.forename: Peter
authors.initials: P
authors.lastname: Ly
authors.forename: Aadil
authors.initials: A
authors.lastname: Kaisani
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Crystal
authors.initials: C
authors.lastname: Cornelius
authors.forename: Woodring E
authors.initials: WE
authors.lastname: Wright
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D003106:Colon / Q000528:radiation effects*; D004249:DNA Damage; D005260:Female; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011839:Radiation, Ionizing; D015398:Signal Transduction
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse