A protective role for HIF-1 in response to redox manipulation and glucose deprivation: implications for tumorigenesis.
Williams KJ., Telfer BA., Airley RE., Peters HPW., Sheridan MR., van der Kogel AJ., Harris AL., Stratford IJ.
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.