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

Sang Bum Kim1, Raj K Pandita, Ugur Eskiocak

  • 1Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 10, 2012
PubMed

Insights

Nuclear factor-erythroid 2-related factor 2 (Nrf2) activation by synthetic triterpenoids protects against ionizing radiation (IR) damage. This Nrf2 activation enhances DNA damage response signaling, reducing chromosome aberrations and improving survival in mice.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Radiation Biology

Background:

  • Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcription factor regulating antioxidant and anti-inflammatory responses.
  • Nrf2 activity is inhibited by Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm.
  • Oxidative stress, like ionizing radiation (IR), disrupts the Nrf2-Keap1 complex, allowing Nrf2 to translocate to the nucleus and induce protective genes.

Purpose of the Study:

  • To investigate the protective mechanisms of Nrf2 activation against IR-induced damage in colonic epithelial cells.
  • To determine if synthetic triterpenoids can activate Nrf2 and confer protection against IR.
  • To evaluate the in vivo efficacy of Nrf2 activation in protecting against IR-induced gastrointestinal toxicity.

Main Methods:

  • Treatment of colonic epithelial cells and mice with synthetic triterpenoids, bardoxolone methyl (BARD) and a derivative.
  • Exposure to ionizing radiation (IR).
  • Assessment of DNA damage, chromosome aberrations, repairosome foci (e.g., Rad51, p53BP1), and survival rates.

Main Results:

  • Bardoxolone methyl (BARD) pretreatment reduced G1 and S/G2 chromosome aberrations after IR.
  • BARD enhanced the resolution of repairosome foci (Rad51, p53BP1) post-IR in a Nrf2-dependent manner.
  • Nrf2 directly binds to antioxidant responsive elements in the p53 binding protein-1 promoter after BARD treatment.
  • A synthetic triterpenoid derivative protected mice from IR-induced DNA damage and gastrointestinal toxicity, improving survival.

Conclusions:

  • Nrf2 activation by synthetic triterpenoids protects colonic epithelial cells from IR-induced damage by enhancing DNA damage response signaling.
  • Nrf2 directly regulates the expression of key DNA damage response proteins like p53 binding protein-1.
  • Synthetic triterpenoids targeting Nrf2 represent a promising strategy for protecting the gastrointestinal tract against acute radiation injury.

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