title: Ethanol enhances arsenic-induced cyclooxygenase-2 expression via both NFAT and NF-κB signalings in colorectal cancer cells.
abstract: Arsenic is a known carcinogen to humans, and chronic exposure to environmental arsenic is a worldwide health concern. As a dietary factor, ethanol carries a well-established risk for malignancies, but the effects of co-exposure to arsenic and ethanol on tumor development are not well understood. In the present study, we hypothesized that ethanol would enhance the function of an environmental carcinogen such as arsenic through increase in COX-2 expression. Our in vitro results show that ethanol enhanced arsenic-induced COX-2 expression. We also show that the increased COX-2 expression associates with intracellular ROS generation, up-regulated AKT signaling, with activation of both NFAT and NF-κB pathways. We demonstrate that antioxidant enzymes have an inhibitory effect on arsenic/ethanol-induced COX-2 expression, indicating that the responsive signaling pathways from co-exposure to arsenic and ethanol relate to ROS generation. In vivo results also show that co-exposure to arsenic and ethanol increased COX-2 expression in mice. We conclude that ethanol enhances arsenic-induced COX-2 expression in colorectal cancer cells via both the NFAT and NF-κB pathways. These results imply that, as a common dietary factor, ethanol ingestion may be a compounding risk factor for arsenic-induced carcinogenesis/cancer development.
authors.affiliation: Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: John Andrew
authors.initials: JA
authors.lastname: Hitron
authors.affiliation: Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: James T F
authors.initials: JT
authors.lastname: Wise
authors.affiliation: Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.affiliation: Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Ram Vinod
authors.initials: RV
authors.lastname: Roy
authors.affiliation: Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Donghern
authors.initials: D
authors.lastname: Kim
authors.affiliation: Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Dai
authors.affiliation: Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Poyil
authors.initials: P
authors.lastname: Pratheeshkumar
authors.affiliation: Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.affiliation: Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.affiliation: Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA. Electronic address: xshi5@uky.edu.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism*; D018053:Arsenites / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D000431:Ethanol / Q000633:toxicity*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects*; D017670:Sodium Compounds / Q000633:toxicity*
chemical_list: D018053:Arsenites; D002274:Carcinogens, Environmental; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; D000431:Ethanol; C017947:sodium arsenite; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: Arsenic; COX-2; Ethanol; NF-κB; NFAT