title: Nitric oxide-mediated bcl-2 stabilization potentiates malignant transformation of human lung epithelial cells.
abstract: Hexavalent chromium (Cr(VI)) compounds are known human carcinogens associated with the incidence of lung cancer. Although a direct correlation between Cr(VI) exposure and lung cancer has been established, several studies aimed at generating animal models for Cr(VI) have yielded inconsistent data that do not affirmatively support findings from epidemiologic studies. Because the lack of a good animal model has hindered the identification of molecular mechanisms involved in Cr(VI) exposure, we developed an in vitro model that facilitates mechanistic studies of Cr(VI)-induced carcinogenesis. We report here that long-term exposure to Cr(VI) leads to the malignant transformation of nontumorigenic human lung epithelial cells. Cr(VI)-transformed cells exhibited loss of contact inhibition, colony formation, and increased rates of cell invasion, migration, and proliferation, as compared with passage-matched control cells. Cr(VI)-transformed cells evaded apoptosis by a mechanism involving S-nitrosylation and stabilization of Bcl-2 protein in a nitric oxide-dependent manner. This study establishes an important in vitro model that facilitates mechanistic studies of Cr(VI)-induced carcinogenesis, and elucidates a novel mechanism that causes apoptosis-resistant malignant transformation of nontumorigenic lung cells in response to a human carcinogen.
authors: Department of Pharmaceutical Sciences, Hampton University, Hampton, Virginia 23668, USA. neelam.azad@hamptonu.edu
authors: Neelam
authors: N
authors: Azad
authors: Anand Krishnan V
authors: AK
authors: Iyer
authors: Liying
authors: L
authors: Wang
authors: Yongju
authors: Y
authors: Lu
authors: Djordje
authors: D
authors: Medan
authors: Vincent
authors: V
authors: Castranova
authors: Yon
authors: Y
authors: Rojanasakul
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D002857:Chromium / Q000633:toxicity; D003545:Cysteine / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008168:Lung / Q000473:pathology*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism*; D009603:Nitroso Compounds / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D009603:Nitroso Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D002857:Chromium; D013481:Superoxides; D009569:Nitric Oxide; D053453:Caspase 9; D003545:Cysteine