Carcinogenesis, Vol. 20, No. 9, 1819-1823,
September 1999
© 1999 Oxford University Press
Carcinogenesis |
Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors
Nelson Institute of Environmental Medicine and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, NY 10016 and
1 Medicine Branch, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA
Nickel (Ni) compounds are potent carcinogens and can induce malignant transformation of rodent and human cells. In an attempt to unravel the molecular mechanisms of Ni-induced transformation we investigated transcriptional activity of hypoxia-inducible factor (HIF-1) and p53 tumor suppressor protein in Ni-transformed cells. We demonstrated that the activity of HIF-1-responsive promoters was increased in Ni-transformed rodent cells resulting in the increased ratio between HIF-1- and p53-stimulated transcription. To further elucidate the roles of HIF-1 and p53 in Ni-induced transformation we used human osteosarcoma (HOS) cells and a Ni-transformed derivative, SA-8 cells. Since non-functional p53 was expressed in both HOS and SA-8 cells, acute Ni treatment induced HIF-1
protein and HIF-1-dependent transcription without affecting p53. In MCF-7 and A549, human cancer cells with the wild-type p53, both functional p53 and HIF-1 proteins accumulated following exposure to Ni. The induction of HIF-1 and wild-type p53 by Ni was detected after 6 h and was most pronounced by 24 h. These results suggest that acute Ni treatment causes accumulation of HIF-1 protein and simultaneous accumulation of wild-type, but not mutant, p53. We suggest that the induction of hypoxia-like conditions in Ni-treated cells with subsequent selection for increased HIF-1-dependent transcription is involved in Ni-induced carcinogenesis.
Abbreviations: CHE, Chinese hamster embryo fibroblasts; DFX, deferoxamine mesylate; FBS, fetal bovine serum; HIF-1, hypoxia-inducible factor; MOI, multiplicity of infection; VEGF, vascular-endothelial growth factor
2 To whom correspondence should be addressed Email: salnikow{at}env.med.nyu.edu
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