Carcinogenic metals induce hypoxia-inducible factor-stimulated transcription by reactive oxygen species-independent mechanism.
Nickel (Ni2+) and cobalt (Co2+) mimic hypoxia and were used as a tool to study the role of oxygen sensing and signaling cascades in the regulation of hypoxia-inducible gene expression. These metals can produce oxidative stress; therefore, it was conceivable that reactive oxygen species (ROS) may trigger signaling pathways resulting in the activation of the hypoxia-inducible factor (HIF)-1 transcription factor and up-regulation of hypoxia-related genes. We found that the exposure of A549 cells to Co2+ or Ni2+ produced oxidative stress, and although Co2+ was a more potent producer of ROS than Ni2+, both metals equally increased the expression of Cap43, a hypoxia-regulated gene. The coadministration of hydrogen peroxide with metals induced more ROS; however, this did not further increase the expression of Cap43 mRNA. The free radical scavenger 2-mercaptoethanol completely suppressed ROS generation by CoCl2 and NiCl2 but did not diminish the induced Cap43 gene expression. The activity of the HIF-1 transcription factor as assessed in transient transfection assays was stimulated by Ni2+, hypoxia, and desferrioxamine, but this activation was not diminished when oxidative stress was attenuated nor was HIF-dependent transcription enhanced by hydrogen peroxide. We conclude that ROS are produced during the exposure of cells to metals that mimic hypoxia, but the formation of ROS was not involved in the activation of HIF-1-dependent genes.
Nelson Institute of Environmental Medicine and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York 10016, USA. salnikow@env.med.nyu.edu
K
K
Salnikow
W
W
Su
M V
MV
Blagosklonny
M
M
Costa
D002273:Carcinogens / Q000633:toxicity*; D018797:Cell Cycle Proteins; D015687:Cell Hypoxia / Q000502:physiology*; D003035:Cobalt / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular; D016166:Free Radical Scavengers / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms; D008623:Mercaptoethanol / Q000494:pharmacology; D009532:Nickel / Q000633:toxicity*; D009687:Nuclear Proteins / Q000378:metabolism*; D011506:Proteins / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D002273:Carcinogens; D018797:Cell Cycle Proteins; D003035:Cobalt; D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D008623:Mercaptoethanol; D009532:Nickel; D009687:Nuclear Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C497442:HIF1A protein, human; C022838:nickel chloride; C018021:cobaltous chloride