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
| Autor: | Yu-Tsen Chen, Huang-Hui Chen, Yen-Wen Huang, Ching-Chuan Kuo, Hui-Ju Tsai |
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| Rok vydání: | 2011 |
| Předmět: |
DNA damage
NF-E2-Related Factor 2 Biology medicine.disease_cause Response Elements Biochemistry Antioxidants Lignans Phosphatidylinositol 3-Kinases Physiology (medical) Cell Line Tumor medicine Humans Furans Protein kinase B PI3K/AKT/mTOR pathway chemistry.chemical_classification Reactive oxygen species Cell Death Activator (genetics) Molecular biology Hydroquinones Up-Regulation Oxidative Stress chemistry Cytoprotection Coix Phosphorylation Signal transduction Proto-Oncogene Proteins c-akt Oxidative stress Heme Oxygenase-1 DNA Damage Signal Transduction |
| Zdroj: | Free radical biologymedicine. 52(6) |
| ISSN: | 1873-4596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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