IngentaConnect Nickel-induced transformation shifts the balance between HIF-1 an...

Authors: An W.G.¹; Melillo G.¹; Blagosklonny M.V.¹; Salnikow K.; Costa M.

Source: Carcinogenesis, Volume 20, Number 9, September 1999 , pp. 1819-1823(5)

Abstract:

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 alpha 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 alpha proteins accumulated following exposure to Ni. The induction of HIF-1 alpha 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 alpha 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.

Language: English

Document Type: Original article

Affiliations: 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

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Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors