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Int. J. Mol. Sci. 2014, 15(7), 12149-12165; doi:10.3390/ijms150712149

Nrf2-Mediated HO-1 Induction Coupled with the ERK Signaling Pathway Contributes to Indirect Antioxidant Capacity of Caffeic Acid Phenethyl Ester in HepG2 Cells

Department of Food and Nutrition, Hannam University, Daejeon 305-811, Korea
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Received: 26 May 2014 / Revised: 17 June 2014 / Accepted: 25 June 2014 / Published: 9 July 2014
(This article belongs to the Special Issue Bioactive Phenolics and Polyphenols)
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Abstract

The objective of this study is to investigate the contributing effect of the nuclear transcription factor-erythroid 2-related factor 2 (Nrf2)-mediated signaling pathway on the indirect antioxidant capacity of caffeic acid phenethyl ester (CAPE) against oxidative stress in HepG2 cells. The result of an antioxidant response element (ARE)-luciferase assay showed that CAPE stimulated ARE promoter activity resulting in increased transcriptional and translational activities of heme oxygenase-1 (HO-1). In addition, CAPE treatment enhanced Nrf2 accumulation in the nucleus and the post-translational phosphorylation level of extracellular signal-regulated kinase (ERK) among several protein kinases tested. Treatment with ERK inhibitor U126 completely suppressed CAPE-induced ERK phosphorylation and HO-1 expression, but it only partly inhibited CAPE-induced Nrf2 accumulation and ARE promoter. Using the 2',7'-dichlorofluorescein-diacetate (DCFH-DA) method, the cellular antioxidant capacity of CAPE against 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH)- or H2O2-induced oxidative stress also was shown to be partially suppressed by the ERK inhibitor. From the overall results it is proposed that the indirect antioxidant activity of CAPE against oxidative stress in HepG2 cells is partially attributed to induction of HO-1, which is regulated by Kelch-like erythroid-cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1)-independent Nrf2 activation relying on post-translational phosphorylation of ERK. View Full-Text
Keywords: caffeic acid phenethyl ester (CAPE); indirect antioxidant activity; heme oxygenase 1 (HO-1); nuclear transcription factor-erythroid 2-related factor 2 (Nrf2) accumulation; ERK (extracellular signal-regulated kinase) phosphorylation caffeic acid phenethyl ester (CAPE); indirect antioxidant activity; heme oxygenase 1 (HO-1); nuclear transcription factor-erythroid 2-related factor 2 (Nrf2) accumulation; ERK (extracellular signal-regulated kinase) phosphorylation
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Kim, J.-K.; Jang, H.-D. Nrf2-Mediated HO-1 Induction Coupled with the ERK Signaling Pathway Contributes to Indirect Antioxidant Capacity of Caffeic Acid Phenethyl Ester in HepG2 Cells. Int. J. Mol. Sci. 2014, 15, 12149-12165.

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