title: Antioncogenic and Oncogenic Properties of Nrf2 in Arsenic-induced Carcinogenesis.
abstract: Arsenic (As(3+)) is a carcinogen with considerable environmental and occupational relevancy. The present study shows that As(3+)-transformed human lung bronchial epithelial BEAS-2B cells (AsT cells) exhibit the property of apoptosis resistance. The level of basal reactive oxygen species (ROS) is very low in AsT cells in correlation with elevated expressions of both antioxidant enzymes and antiapoptotic proteins. Nuclear factor erythroid 2-related factor (Nrf2) and p62 are constitutively expressed. These two proteins up-regulate antioxidant enzymes and antiapoptotic proteins. The knockdown of Nrf2 or p62 by small interfering RNA (siRNA) enhanced both ROS levels and As(3+)-induced apoptosis in transformed cells. AsT cells have autophagy deficiency as evidenced by reduced formation of microtubule-associated protein 1 light chain 3 (LC3)-II, GFP-LC3 puncta, and autophagy flux. Results obtained using a soft agar assay and shRNA Nrf2-transfected cells show that Nrf2 plays an antioncogenic role before transformation, whereas this transcription factor plays an oncogenic role after transformation. In addition, depletion of Nrf2 by shRNA dramatically inhibited growth and proliferation of transformed cells. Furthermore, the Nrf2 protein levels and antiapoptotic and antioxidant enzyme levels are higher in lung adenocarcinoma than in normal tissues. Collectively, this study demonstrates that a constitutively high level of Nrf2 in AsT cells up-regulates the antioxidant proteins catalase and superoxide dismutase as well as the antiapoptotic proteins Bcl-2 and Bcl-xL. The final consequences are decreased ROS generation and increased apoptotic resistance, cell survival and proliferation, and tumorigenesis.
authors.affiliation: Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305; Departments of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
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, Kentucky 40536-0305; Departments of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
authors.forename: Poyil
authors.initials: P
authors.lastname: Pratheeshkumar
authors.affiliation: Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305; Departments of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
authors.forename: Ram Vinod
authors.initials: RV
authors.lastname: Roy
authors.affiliation: Departments of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
authors.forename: John Andrew
authors.initials: JA
authors.lastname: Hitron
authors.affiliation: Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305; Departments of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Departments of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
authors.forename: Sasidharan Padmaja
authors.initials: SP
authors.lastname: Divya
authors.affiliation: Departments of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.affiliation: Departments of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.affiliation: Departments of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Departments of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305; Departments of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305. Electronic address: xshi5@email.uky.edu.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D001151:Arsenic / Q000633:toxicity*; D001343:Autophagy; D063646:Carcinogenesis / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D001151:Arsenic; D002374:Catalase; D051267:NF-E2-Related Factor 2; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D051020:bcl-X Protein; D000099156:Superoxide Dismutase 2; C494811:BCL2L1 protein, human; C495635:NFE2L2 protein, human; C118585:P62 protein, human
keywords: apoptosis; arsenic; nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); p62 (sequestosome 1 (SQSTM1)); reactive oxygen species (ROS); transformation