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Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway

John D Hayes1, Michael McMahon, Sudhir Chowdhry

  • 1Biomedical Research Institute, Ninewells Hospital, University of Dundee, Scotland, United Kingdom. j.d.hayes@dundee.ac.uk

Antioxidants & Redox Signaling
|May 8, 2010
PubMed

Insights

Chemopreventive agents activate the Nrf2 (cap

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Pharmacology

Background:

  • The cap'n'collar (CNC) bZIP transcription factor Nrf2 regulates genes involved in cellular defense against oxidative and electrophilic stress.
  • Nrf2 activity is tightly controlled by Keap1-dependent ubiquitylation and proteasomal degradation under homeostatic conditions.
  • Many chemopreventive compounds, including synthetic chemicals and phytochemicals, induce Nrf2-target genes, suggesting a role in adaptive cellular responses.

Purpose of the Study:

  • To review synthetic compounds and phytochemicals that activate the Nrf2 pathway.
  • To discuss the mechanism of Nrf2 activation by chemopreventive agents, focusing on the role of Keap1.
  • To explore the diversity of antioxidant response elements (AREs) and species-specific differences in Nrf2-regulated gene expression.

Main Methods:

  • Review of existing literature on Nrf2 regulation, chemopreventive agents, and ARE structure.
  • Analysis of the redox-sensitive nature of Keap1 and its interaction with Nrf2.
  • Discussion of critical cysteine residues in Keap1 involved in Nrf2 de-repression.

Main Results:

  • Chemopreventive agents, often thiol-reactive, disrupt the Keap1-Nrf2 interaction, leading to Nrf2 stabilization and nuclear accumulation.
  • Activated Nrf2 heterodimerizes with Maf proteins to transactivate genes containing AREs.
  • Evidence suggests distinct classes of ARE sequences and species-specific variations in the ARE-gene battery.

Conclusions:

  • Compounds that induce Nrf2-target genes represent a promising strategy for cancer chemoprevention.
  • Understanding the Keap1-Nrf2 pathway and ARE structure is crucial for developing effective Nrf2-activating agents.
  • Further research into species differences and critical Keap1 residues can refine therapeutic strategies.

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