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Nrf2/ARE pathway activation, HO-1 and NQO1 induction by polychlorinated biphenyl quinone is associated with reactive oxygen species and PI3K/AKT signaling.
Chem Biol Interact. 2014 Feb 25; 209:56-67.CB

Abstract

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 Keap1 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 Keap1 expression in nucleus suggested the dissociation of Nrf2/Keap1 complex. Similarly, mRNA level of Nrf2 was elevated significantly with PCB29-pQ treatment, but not Keap1. 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-3β was down-regulated. Pretreatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), suppressed the phosphorylation of AKT and inhibited PCB29-pQ induced Nrf2/HO-1 activation, meanwhile, GSK-3β 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 AKT pathway but not MAPK signaling, the activation of Nrf2/ARE may be an adaptive response to oxidative stress.

Authors+Show Affiliations

Key Laboratory of Luminescence and Real-Time Analysis, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.Key Laboratory of Luminescence and Real-Time Analysis, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.Key Laboratory of Luminescence and Real-Time Analysis, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.Key Laboratory of Luminescence and Real-Time Analysis, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.Key Laboratory of Luminescence and Real-Time Analysis, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.Key Laboratory of Luminescence and Real-Time Analysis, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China. Electronic address: ysong@swu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24361488

Citation

Li, Lingrui, et al. "Nrf2/ARE Pathway Activation, HO-1 and NQO1 Induction By Polychlorinated Biphenyl Quinone Is Associated With Reactive Oxygen Species and PI3K/AKT Signaling." Chemico-biological Interactions, vol. 209, 2014, pp. 56-67.
Li L, Dong H, Song E, et al. Nrf2/ARE pathway activation, HO-1 and NQO1 induction by polychlorinated biphenyl quinone is associated with reactive oxygen species and PI3K/AKT signaling. Chem Biol Interact. 2014;209:56-67.
Li, L., Dong, H., Song, E., Xu, X., Liu, L., & Song, Y. (2014). Nrf2/ARE pathway activation, HO-1 and NQO1 induction by polychlorinated biphenyl quinone is associated with reactive oxygen species and PI3K/AKT signaling. Chemico-biological Interactions, 209, 56-67. https://doi.org/10.1016/j.cbi.2013.12.005
Li L, et al. Nrf2/ARE Pathway Activation, HO-1 and NQO1 Induction By Polychlorinated Biphenyl Quinone Is Associated With Reactive Oxygen Species and PI3K/AKT Signaling. Chem Biol Interact. 2014 Feb 25;209:56-67. PubMed PMID: 24361488.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nrf2/ARE pathway activation, HO-1 and NQO1 induction by polychlorinated biphenyl quinone is associated with reactive oxygen species and PI3K/AKT signaling. AU - Li,Lingrui, AU - Dong,Hui, AU - Song,Erqun, AU - Xu,Xiaoyu, AU - Liu,Lichao, AU - Song,Yang, Y1 - 2013/12/17/ PY - 2013/10/10/received PY - 2013/11/26/revised PY - 2013/12/09/accepted PY - 2013/12/24/entrez PY - 2013/12/24/pubmed PY - 2014/4/15/medline KW - HO-1 KW - Keap1 KW - MAPK KW - NQO1 KW - PCB KW - ROS SP - 56 EP - 67 JF - Chemico-biological interactions JO - Chem Biol Interact VL - 209 N2 - 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 Keap1 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 Keap1 expression in nucleus suggested the dissociation of Nrf2/Keap1 complex. Similarly, mRNA level of Nrf2 was elevated significantly with PCB29-pQ treatment, but not Keap1. 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-3β was down-regulated. Pretreatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), suppressed the phosphorylation of AKT and inhibited PCB29-pQ induced Nrf2/HO-1 activation, meanwhile, GSK-3β 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 AKT pathway but not MAPK signaling, the activation of Nrf2/ARE may be an adaptive response to oxidative stress. SN - 1872-7786 UR - https://www.unboundmedicine.com/medline/citation/24361488/Nrf2/ARE_pathway_activation_HO_1_and_NQO1_induction_by_polychlorinated_biphenyl_quinone_is_associated_with_reactive_oxygen_species_and_PI3K/AKT_signaling_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0009-2797(13)00326-8 DB - PRIME DP - Unbound Medicine ER -