期刊
CHEMICO-BIOLOGICAL INTERACTIONS
卷 209, 期 -, 页码 56-67出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2013.12.005
关键词
PCB; ROS; Keap1; NQO1; HO-1; MAPK
资金
- National Natural Science Foundation of China (NSFC) [21005064, 21035005]
- Scientific Research Foundation for the Returned Overseas Chinese Scholars
- State Education Ministry [2011[508]]
- Fundamental Research Funds for the Central Universities [XDJK2010B008, XDJK2013B009]
Nrf2/ARE pathway plays an important role in adapt to oxidative stress caused by pro-oxidants and electrophiles through up-regulating phase II detoxifying enzymes. Our previous study has demonstrated that PCB quinone exposure causes severe cellular oxidative stress (Toxicology In Vitro 26 (2012) 841-848). There are no reports describing the ability of PCB quinone on Nrf2/ARE activation. In the present study, we found that exposure to PCB29-pQ resulted in a significant increase in Nrf2 and Keapl expression in total protein, as well as the Nrf2 targeting genes, including NQO1 and HO-1. Next, immunocytochemistry analysis identified the accumulation of Nrf2 in nucleus subsequent to PCB29-pQ treatment. The increased Nrf2 and constant Keapl expression in nucleus suggested the dissociation of Nrf2/Keap1 complex. Similarly, mRNA level of Nrf2 was elevated significantly with PCB29-pQ treatment, but not Keapl. Additionally, PCB29-pQ treatment led to significant up-regulation of the mRNA level of antioxidant enzymes, NQO1 and HO-1, in a concentration-dependent manner. Electrophoretic mobility shift assay and luciferase reporter assay further confirmed the formation of Nrf2-ARE complex. PCB29-pQ treatment has no effect on mitogen-activated protein kinase signaling, however, phospho-AKT was up-regulated and GSK-3p was down-regulated. Pretreatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), suppressed the phosphorylation of ART and inhibited PCB29-pQ induced Nrf2/HO-1 activation, meanwhile, GSK-30 expression was increased accordingly. At last, reactive oxygen species (ROS) scavengers inhibited PCB29-pQ induced Nrf2 activation partly. These results suggested that Nrf2 activation by PCB29-pQ in HepG2 cells is associated with ROS and ART pathway but not MAPK signaling, the activation of NI-f2/ARE may be an adaptive response to oxidative stress. (c) 2013 Elsevier Ireland Ltd. All rights reserved.
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