Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation

Sang Bum Kim, Raj K. Pandita, Ugur Eskiocak, Peter Ly, Aadil Kaisani, Rakesh Kumar, Crystal Cornelius, Woodring E. Wright, Tej K. Pandita, Jerry W. Shay

Research output: Contribution to journalArticle

71 Scopus citations

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 proteinwith CNC homology)-associated protein 1, in the cytoplasmunder 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, bardoxolonemethyl (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.

Original languageEnglish (US)
Pages (from-to)E2949-E2955
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number43
DOIs
StatePublished - Oct 23 2012

Keywords

  • Antioxidant anti-inflammatory modulators (AIMs)
  • Enhanced DNA repair
  • Radioprotection

ASJC Scopus subject areas

  • General

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