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Molecules. 2017 Jun 10;22(6). pii: E969. doi: 10.3390/molecules22060969.

Docosahexaenoic Acid Induces Expression of Heme Oxygenase-1 and NAD(P)H:quinone Oxidoreductase through Activation of Nrf2 in Human Mammary Epithelial Cells.

Author information

1
Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826 Korea. bangdeng1126@naver.com.
2
Cancer Research Institute, Seoul National University, Seoul 03080, Korea. bangdeng1126@naver.com.
3
Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826 Korea. qorwh7@snu.ac.kr.
4
Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826 Korea. Saeidi@snu.ac.kr.
5
Department of Molecular Medicine and Biopharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea. Saeidi@snu.ac.kr.
6
Department of Food and Nutrition, College of Human Ecology, Sungshin Women's University, Seoul 01133, Korea. nhkdec28@gmail.com.
7
Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826 Korea. surh@snu.ac.kr.
8
Cancer Research Institute, Seoul National University, Seoul 03080, Korea. surh@snu.ac.kr.
9
Department of Molecular Medicine and Biopharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea. surh@snu.ac.kr.

Abstract

Docosahexaenoic acid (DHA), an ω-3 fatty acid abundant in fish oils, has diverse health beneficial effects, such as anti-oxidative, anti-inflammatory, neuroprotective, and chemopreventive activities. In this study, we found that DHA induced expression of two representative antioxidant/cytoprotective enzymes, heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase (NQO1), in human mammary epithealial (MCF-10A) cells. DHA-induced upregulation of these enzymes was accompanied by enhanced translocation of the redox-sensitive transcription factor Nrf2 into the nucleus and its binding to antioxidant response element. Nrf2 gene silencing by siRNA abolished the DHA-induced expression of HO-1 and NQO1 proteins. When MCF-10A cells were transfected with mutant constructs in which the cysteine 151 or 288 residue of Keap1 was replaced by serine, DHA-induced expression of HO-1 and NQO1 was markedly reduced. Moreover, DHA activated protein kinase C (PKC)δ and induced Nrf2 phosphorylation. DHA-induced phosphorylation of Nrf2 was abrogated by the pharmacological PKCδ inhibitor rottlerin or siRNA knockdown of its gene expression. The antioxidants N-acetyl-l-cysteine and Trolox attenuated DHA-induced activation of PKCδ, phosphorylation of Nrf2, and and its target protein expression. In conclusion, DHA activates Nrf2, possibly through modification of critical Keap1 cysteine 288 residue and PKCδ-mediated phosphorylation of Nrf2, leading to upregulation of HO-1 and NQO1 expression.

KEYWORDS:

NAD(P)H:quinone oxidoreductase; docosahexaenoic acid; heme oxygenase-1; nrf2; ω-3 polyunsaturated fatty acids

PMID:
28604588
PMCID:
PMC6152628
DOI:
10.3390/molecules22060969
[Indexed for MEDLINE]
Free PMC Article

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