Journal article
Ligand-independent activation of aryl hydrocarbon receptor signaling in PCB3-quinone treated HaCaT human keratinocytes
Toxicology letters, Vol.233(3), pp.258-266
03/18/2015
DOI: 10.1016/j.toxlet.2015.02.005
PMCID: PMC4341842
PMID: 25668756
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.
Details
- Title: Subtitle
- Ligand-independent activation of aryl hydrocarbon receptor signaling in PCB3-quinone treated HaCaT human keratinocytes
- Creators
- Wusheng Xiao - Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, B180 Medical Laboratories, Iowa City, IA 52242, USAJyungmean Son - Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, B180 Medical Laboratories, Iowa City, IA 52242, USASabine U Vorrink - Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, B180 Medical Laboratories, Iowa City, IA 52242, USAFrederick E Domann - Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, B180 Medical Laboratories, Iowa City, IA 52242, USAPrabhat C Goswami - 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
- Resource Type
- Journal article
- Publication Details
- Toxicology letters, Vol.233(3), pp.258-266
- DOI
- 10.1016/j.toxlet.2015.02.005
- PMID
- 25668756
- PMCID
- PMC4341842
- NLM abbreviation
- Toxicol Lett
- ISSN
- 0378-4274
- eISSN
- 1879-3169
- Publisher
- Netherlands
- Grant note
- P30 ES005605 / NIEHS NIH HHS P42 ES013661 / NIEHS NIH HHS P42ES013661 / NIEHS NIH HHS R01 CA111365 / NCI NIH HHS 2R01CA111365 / NCI NIH HHS
- Language
- English
- Date published
- 03/18/2015
- Academic Unit
- Pathology; Surgery; Radiation Oncology
- Record Identifier
- 9984047636202771
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