The role of hypoxia-inducible signaling pathway in nickel carcinogenesis.
Using human and rodent cells in vitro, we characterized a hypoxia-inducible signaling pathway as one of the pathways affected by carcinogenic nickel compounds. Acute exposure to nickel activates hypoxia-inducible transcription factor-1 (HIF-1), which strongly induces hypoxia-inducible genes, including the recently discovered tumor marker Cap43. This gene has been cloned based on its nickel inducibility and was found to be highly inducible by hypoxia. To identify other HIF-1-dependent/independent nickel-inducible genes, we used cells obtained from HIF-1 alpha null mouse embryos and analyzed gene expression changes using the microarray technique. We found that genes coding for glycolytic enzymes, known to be regulated by HIF-1, were also induced in nickel-exposed cells. In addition, we identified a number of new genes highly induced by nickel in an HIF-dependent manner. Elevated HIF-1 activity after acute nickel exposure might be selectively advantageous because nickel-transformed rodent and human cells possess increased HIF-1 transcriptional activity. Hypoxia plays an important role in tumor progression. It selects for cells with enhanced glycolytic activity, causing production of large amounts of lactic acid, one of the most common features of tumor cells (Warburg effect). Here, we hypothesize that exposure to nickel activates the hypoxia-inducible pathway and facilitates selection of cells with increased transcriptional activity of hypoxia-inducible genes, which may be important in the nickel-induced carcinogenic process.
Salnikow
Konstantin
K
Nelson Institute of Environmental Medicine, NIEHS Center and Kaplan Comprehensive Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 11016, USA. salnikow@env.med.nyu.edu
Davidson
Todd
T
Costa
Max
M
D000818:Animals; D018797:Cell Cycle Proteins; D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D018450:Disease Progression; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D019344:Lactic Acid / Q000378:metabolism; D009532:Nickel / Q000494:pharmacology / Q000633:toxicity*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis; D011506:Proteins; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D019344:Lactic Acid; D009532:Nickel; D009687:Nuclear Proteins; D011506:Proteins; D014157:Transcription Factors; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C497442:HIF1A protein, human