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We have investigated the role of HIF-1 in the cellular response to redox modulation via the inhibition of oxidative phosphorylation. We demonstrate that manipulation of redox in air, achieved by inhibiting cytochrome oxidase with cyanide, induces HIF-1 mediated transcription in wild-type CHO and HT1080 human tumour cells but not in CHO cells deficient in the oxygen responsive, HIF-1alpha sub-unit of HIF-1. Hypoglycaemia attenuates cyanide-mediated transcription in non-transformed HIF-1 wild-type CHO cells but not the human tumour derived cell line. Cells lacking either HIF-1alpha, or the second composite sub-unit of HIF-1, HIF-1beta, were markedly more sensitive to the combined stress of perturbed redox and hypoglycaemia than wild-type cells. As such conditions together with hypoxia are prevalent in tumours, these data suggest that HIF-1 may have a protective role in adaptation to the tumour micro-environment. In support of this we demonstrate that HIF-1alpha deficient cells are less tumorigenic than wild-type cells. They showed a reduced growth rate when grown as xenografts in nude mice. This was not related to vascular parameters that were identical to those found in HIF-1 wild-type tumours. The HIF-1 deficient tumours lacked focal expression of Glut-1 in hypoxic tumour regions. Compromised glucose uptake and metabolic adaptation to the tumour micro-environment may form the basis of the reduced tumorigenicity associated with these cells.

Original publication

DOI

10.1038/sj.onc.1205047

Type

Journal article

Journal

Oncogene

Publication Date

10/01/2002

Volume

21

Pages

282 - 290

Keywords

Animals, CHO Cells, Cell Survival, Cell Transformation, Neoplastic, Cricetinae, DNA-Binding Proteins, Female, Fibrosarcoma, Glucose, Glucose Transporter Type 1, Humans, Hypoglycemia, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Nude, Monosaccharide Transport Proteins, Mutagenesis, Neovascularization, Pathologic, Nuclear Proteins, Oxidation-Reduction, Transcription Factors, Transplantation, Heterologous, Tumor Cells, Cultured