Document Detail


Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation.
MedLine Citation:
PMID:  23045680     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-10-08
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-24     Completed Date:  2013-01-07     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E2949-55     Citation Subset:  IM    
Affiliation:
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039, USA.
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MeSH Terms
Descriptor/Qualifier:
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*
Grant Support
ID/Acronym/Agency:
P30 CA142543/CA/NCI NIH HHS; R01 CA154320/CA/NCI NIH HHS; R01CA123232/CA/NCI NIH HHS; R01CA129537/CA/NCI NIH HHS; R01CA154320/CA/NCI NIH HHS; U19A1091175//PHS HHS
Chemical
Reg. No./Substance:
0/NF-E2-Related Factor 2; 0/Nfe2l2 protein, mouse
Comments/Corrections

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