Abstract A83: 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: | Huang-Hui Chen, Yu-Tsen Chen, Ching-Chuan Kuo, Hui-Ju Tsai, Yen-Wen Huang |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Molecular Cancer Therapeutics. 10:A83-A83 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.targ-11-a83 |
| Popis: | The Nrf2/ARE pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins, and has been considered as a potential target for cancer chemoprevention by eliminating harmful reactive oxygen species (ROS) or reactive intermediates generated from carcinogens. The objectives of this study were to identify a novel Nrf2/ARE activator 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 the potentially cytoprotective compound. 4-Ketopinoresinol (4-KPR), the (−) double cyclized type of lignan obtained from adlay (Coix lachrymal-jobi L. var. ma-yuen Stapf), more effectively activates ARE-driven luciferase activity 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, and their protein products. 4-KPR suppresses oxidative stress-induced DNA damage and cell death via up-regulation of HO-1. Inhibition of PI3K/AKT signal by chemical inhibitors or RNA interference suppressed Nrf2 activation and HO-1 up-regulation. 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. These results may have relevance to the clinical application of 4-KPR and its significance in cancer chemoprevention. The study was supported by grants of DOH100-TD-C-111-004, NSC98-2320-B-400-003-MY3, and NSC99-2323-B-400-006. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A83. |
| Databáze: | OpenAIRE |
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