title: Ethanol enhances tumor angiogenesis in vitro induced by low-dose arsenic in colon cancer cells through hypoxia-inducible factor 1 alpha pathway.
abstract: Health effects due to environmental exposure to arsenic are a major global health concern. Arsenic has been known to induce carcinogenesis and enhance tumor development via complex and unclear mechanism. Ethanol is also a well-established risk factor for many malignancies. However, little is known about the effects of coexposure to arsenic and ethanol in tumor development. In this study, we investigate the signaling and angiogenic effect of coexposure of arsenic and ethanol on different colon cancer cell lines. Results show that ethanol markedly enhanced arsenic-induced tumor angiogenesis in vitro. These responses are related to intracellular reactive oxygen species (ROS) generation, NADPH oxidase activation, and upregulation of PI3K/Akt and hypoxia-inducible factor 1 alpha (HIF-1α) signaling. We have also found that ethanol increases the arsenic-induced expression and secretion of angiogenic signaling molecules such as vascular endothelial growth factor, which further confirmed the above observation. Antioxidant enzymes inhibited arsenic/ethanol-induced tumor angiogenesis, demonstrating that the responsive signaling pathways of coexposure to arsenic and ethanol are related to ROS generation. We conclude that ethanol is able to enhance arsenic-induced tumor angiogenesis in colorectal cancer cells via the HIF-1α pathway. These results indicate that alcohol consumption should be taken into consideration in the investigation of arsenic-induced carcinogenesis in arsenic-exposed populations.
authors.affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.forename: Songze
authors.initials: S
authors.lastname: Ding
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: John Andrew
authors.initials: JA
authors.lastname: Hitron
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.forename: Jeong-Chae
authors.initials: JC
authors.lastname: Lee
authors.forename: Qinchen
authors.initials: Q
authors.lastname: Lin
authors.forename: Pratheeshkumar
authors.initials: P
authors.lastname: Poyil
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D018053:Arsenites / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D000431:Ethanol / Q000633:toxicity*; D017930:Genes, Reporter; D045325:HCT116 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019899:Paracrine Communication; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D018053:Arsenites; D002273:Carcinogens; D017077:Culture Media, Conditioned; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000431:Ethanol; C017947:sodium arsenite; D002374:Catalase; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt