title: Hexavalent chromium Cr(VI) up-regulates COX-2 expression through an NFκB/c-Jun/AP-1-dependent pathway.
abstract: BACKGROUND
  Hexavalent chromium [Cr(VI)] is recognized as a human carcinogen via inhalation. However, the molecular mechanisms by which Cr(VI) causes cancers are not well understood.
  
  
  OBJECTIVE
  We evaluated cyclooxygenase-2 (COX-2) expression and the signaling pathway leading to this induction due to Cr(VI) exposure in cultured cells.
  
  
  METHODS
  We used the luciferase reporter assay and Western blotting to determine COX-2 induction by Cr(VI). We used dominant negative mutant, genetic knockout, gene knockdown, and chromatin immunoprecipitation approaches to elucidate the signaling pathway leading to COX-2 induction.
  
  
  RESULTS
  We found that Cr(VI) exposure induced COX-2 expression in both normal human bronchial epithelial cells and mouse embryonic fibroblasts in a concentration- and time-dependent manner. Deletion of IKKβ [inhibitor of transcription factor NFκB (IκB) kinase β; an upstream kinase responsible for nuclear factor κB (NFκB) activation] or overexpression of TAM67 (a dominant-negative mutant of c-Jun) dramatically inhibited the COX-2 induction due to Cr(VI), suggesting that both NFκB and c-Jun/AP-1 pathways were required for Cr(VI)-induced COX-2 expression. Our results show that p65 and c-Jun are two major components involved in NFκB and AP-1 activation, respectively. Moreover, our studies suggest crosstalk between NFκB and c-Jun/AP-1 pathways in cellular response to Cr(VI) exposure for COX-2 induction.
  
  
  CONCLUSIONS
  We demonstrate for the first time that Cr(VI) is able to induce COX-2 expression via an NFκB/c-Jun/AP-1-dependent pathway. Our results provide novel insight into the molecular mechanisms linking Cr(VI) exposure to lung inflammation and carcinogenesis.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Zuo
authors.forename: Tongjian
authors.initials: T
authors.lastname: Cai
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Yu
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D002857:Chromium / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004586:Electrophoresis; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D002273:Carcinogens; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D002857:Chromium; C074702:chromium hexavalent ion; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2