4-Ketopinoresinol, a novel naturally occurring ARE activator, induces the Nrf2/HO-1 axis and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling

Free Radic Biol Med. 2012 Mar 15;52(6):1054-66. doi: 10.1016/j.freeradbiomed.2011.12.012. Epub 2011 Dec 24.

Abstract

The Nrf2/ARE pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins and has been considered a potential target for cancer chemoprevention because it eliminates harmful reactive oxygen species or reactive intermediates generated from carcinogens. The objectives of this study were to identify novel Nrf2/ARE activators and to investigate the mechanistic signaling pathway involved in the activation of Nrf2-mediated cytoprotective effects against oxidative-induced cell injury. A stable ARE-driven luciferase reporter cell line was established to screen a potentially cytoprotective compound. 4-Ketopinoresinol (4-KPR), the (α-γ) double-cyclized type of lignan obtained from adlay (Coix lachryma-jobi L. var. ma-yuen Stapf), activates ARE-driven luciferase activity more effectively than the classical ARE activator tert-butylhydroquinone. 4-KPR treatment resulted in a transient increase in AKT phosphorylation and subsequent phosphorylation and nuclear translocation of Nrf2, along with increased expression of ARE-dependent cytoprotective genes, such as heme oxygenase-1 (HO-1), aldo-keto reductases, and glutathione synthetic enzyme. 4-KPR suppresses oxidative stress-induced DNA damage and cell death via upregulation of HO-1. Inhibition of PI3K/AKT signaling by chemical inhibitors or RNA interference not only suppressed 4-KPR-induced Nrf2/HO-1 activation, but also eliminated the cytoprotective effect against oxidative damage. These observations in an ARE-regulated gene system suggest that 4-KPR is a novel Nrf2/ARE-mediated transcription activator, activates the Nrf2/HO-1 axis, and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Coix
  • Cytoprotection*
  • DNA Damage / drug effects
  • Furans / chemistry
  • Furans / pharmacology
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Hydroquinones / pharmacology
  • Lignans / chemistry
  • Lignans / pharmacology*
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Response Elements / genetics
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects

Substances

  • 4-ketopinoresinol
  • Antioxidants
  • Furans
  • Hydroquinones
  • Lignans
  • NF-E2-Related Factor 2
  • 2-tert-butylhydroquinone
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt