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: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 43 Pg. E2949-55 (Oct 23 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 23045680 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse

Topics

• Animals
• Cell Line, Transformed
• Colon (radiation effects)
• DNA Damage
• Female
• Immunohistochemistry
• Intestinal Mucosa (radiation effects)
• Mice
• Mice, Inbred C57BL
• NF-E2-Related Factor 2 (metabolism)
• Radiation, Ionizing
• Signal Transduction