Oncotarget

Research Papers:

Methylseleninic acid induces NAD(P)H:quinone oxidoreductase-1 expression through activation of NF-E2-related factor 2 in Chang liver cells

Jong-Min Park _, Do-Hee Kim, Hye-Kyung Na and Young-Joon Surh

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Oncotarget. 2018; 9:3014-3028. https://doi.org/10.18632/oncotarget.10289

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Abstract

Jong-Min Park1, Do-Hee Kim1, Hye-Kyung Na2, Young-Joon Surh1,3

1Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea

2Department of Food and Nutrition, College of Human Ecology, Sungshin Women's University, Seoul, South Korea

3Cancer Research Institute, Seoul National University, Seoul, South Korea

Correspondence to:

Young-Joon Surh, email: [email protected], [email protected]

Keywords: selenium, Nrf2, methylseleninic acid, chemoprevention

Received: November 01, 2015     Accepted: May 06, 2016     Published: June 25, 2016

ABSTRACT

Selenium has been reported to induce the expression of some cytoprotective enzymes, which may account for its chemoprotective and chemopreventive effects. However, it remains largely unresolved whether these effects are exerted by selenium itself or mediated by its metabolite(s). In the present study, methylseleninic acid (MSeA), a monomethylated selenium, induced the expression of NAD(P)H:quinone oxidoreductase-1 (NQO-1) in human Chang liver cells. Expression of NQO-1 and other antioxidant/stress response genes is primarily regulated by the transcription factor NF-E2-related factor2 (Nrf2). Exposure of human Chang liver cells to MSeA (3 μM) increased nuclear translocation of Nrf2 and binding to antioxidant response elements. Silencing Nrf2 markedly reduced the MSeA-induced NQO-1 expression. In comparison with embryonic fibroblasts from Nrf2 wild-type mice, those from Nrf2 knockout mice failed to induce NQO-1 expression when treated with MSeA. Moreover, MSeA treatment enhanced ubiquitination of Keap1, but repressed Nrf2 ubiquitination. Pretreatment of cells with dithiothreitol abrogated the MSeA-induced NQO-1 expression, suggesting that MSeA causes Keap1 thiol modification. MSeA-induced NQO-1 upregulation was attenuated in cells harbouring the mutant Keap1 in which the cysteine 151 residue was replaced by serine. Oral administration of MSeA (1 mg/kg) by gavage to mice induced hepatic NQO-1 expression. Similar to MSeA, methylselenol generated from selenomethionine by methioninase activity induced NQO-1 expression. In conclusion, MSeA, the immediate precursor of methylselenol, upregulates the expression of NQO-1 via the Keap1-Nrf2 signaling. The above findings suggest that biological activities of selenium are dependent on the nature of the metabolites as well as the type of ingested selenium formulations.


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