title: 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.
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.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
authors.forename: Huang-Hui
authors.initials: HH
authors.lastname: Chen
authors.forename: Yu-Tsen
authors.initials: YT
authors.lastname: Chen
authors.forename: Yen-Wen
authors.initials: YW
authors.lastname: Huang
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Tsai
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Kuo
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D031742:Coix; D019610:Cytoprotection; D004249:DNA Damage / Q000187:drug effects; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C572940:4-ketopinoresinol; D000975:Antioxidants; D005663:Furans; D006873:Hydroquinones; D017705:Lignans; D051267:NF-E2-Related Factor 2; C018855:2-tert-butylhydroquinone; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt