title: Ligand-independent activation of aryl hydrocarbon receptor signaling in PCB3-quinone treated HaCaT human keratinocytes.
abstract: Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that plays a critical role in metabolism, cell proliferation, development, carcinogenesis, and xenobiotic response. In general, dioxin-like polychlorinated biphenyls (PCBs) exhibit a ligand-dependent activation of AhR-signaling. Results from this study show that a quinone-derivative (1-(4-Chlorophenyl)-benzo-2,5-quinone; 4-ClBQ) of a non-dioxin like PCB (PCB3) also activates AhR-signaling. Treatments of HaCaT human keratinocytes with 4-ClBQ and dioxin-like PCB126 significantly increased AhR-target gene expression, CYP1A1 mRNA and protein levels. 4-ClBQ-induced increase CYP1A1 expression was associated with an increase in the nuclear translocation of AhR protein as well as an increase in the luciferase-reporter activity of a human CYP1A1 xenobiotic response element (XRE). 6,2',4'-Trimethoxyflavone (TMF), a well-characterized AhR-ligand antagonist significantly suppressed PCB126-induced increase in CYP1A1 expression, while the same treatment did not suppress 4-ClBQ-induced increase in CYP1A1 expression. However, siRNA-mediated down-regulation of AhR significantly inhibited 4-ClBQ-induced increase in CYP1A1 expression, suggesting that AhR mediates 4-ClBQ-induced increase in CYP1A1 expression. Interestingly, treatment with the antioxidant N-acetyl-l-cysteine significantly suppressed 4-ClBQ-induced increase in CYP1A1 expression. Furthermore, CYP1A1 expression also increased in cells treated with hydrogen peroxide. These results demonstrate that a ligand-independent and oxidative stress dependent pathway activates AhR-signaling in 4-ClBQ treated HaCaT cells. Because AhR signaling is believed to mediate xenobiotics response, our results may provide a mechanistic rationale for the use of antioxidants as effective countermeasure to environmental pollutant-induced adverse health effects.
authors: Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, B180 Medical Laboratories, Iowa City, IA 52242, USA.
authors: Wusheng
authors: W
authors: Xiao
authors: Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, B180 Medical Laboratories, Iowa City, IA 52242, USA.
authors: Jyungmean
authors: J
authors: Son
authors: Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, B180 Medical Laboratories, Iowa City, IA 52242, USA.
authors: Sabine U
authors: SU
authors: Vorrink
authors: Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, B180 Medical Laboratories, Iowa City, IA 52242, USA.
authors: Frederick E
authors: FE
authors: Domann
authors: Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, B180 Medical Laboratories, Iowa City, IA 52242, USA. Electronic address: prabhat-goswami@uiowa.edu.
authors: Prabhat C
authors: PC
authors: Goswami
mesh_terms: D021581:Active Transport, Cell Nucleus; D016227:Benzoquinones / Q000633:toxicity*; D001713:Biphenyl Compounds / Q000633:toxicity; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D047309:Flavones / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D008024:Ligands; D018384:Oxidative Stress; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C000597136:1-(4-chlorophenyl)-benzo-2,5-quinone; C546607:6,2',4'-trimethoxyflavone; D016227:Benzoquinones; D001713:Biphenyl Compounds; D047309:Flavones; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D011078:Polychlorinated Biphenyls; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; C006983:4-chlorobiphenyl; C023035:3,4,5,3',4'-pentachlorobiphenyl
keywords: AhR; CYP1A1; HaCaT cells; Polychlorinated biphenyls; Quinone