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A protective role for HIF-1 in response to redox manipulation and glucose deprivation: implications for tumorigenesis

Williams, Kaye J, Telfer, Brian A, Airley, Rachel, Peters, Hans PW, Sheridan, Mary R, van der Kogel, Albert J, Harris, Adrian L. and Stratford, Ian J (2002) A protective role for HIF-1 in response to redox manipulation and glucose deprivation: implications for tumorigenesis. Oncogene, 21 (2). pp. 282-290. ISSN 0950-9232

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Abstract

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-1 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-1, or the second composite sub-unit of HIF-1, HIF-1, 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-1 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. Compromized glucose uptake and metabolic adaptation to the tumour micro-environment may form the basis of the reduced tumorigenecity associated with these cells.

Item Type: Article
Subjects: Q Science > Q Science (General)
Q Science > QP Physiology
Schools: School of Applied Sciences
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Depositing User: Sharon Beastall
Date Deposited: 08 Jul 2010 09:58
Last Modified: 09 Sep 2010 09:29
URI: http://eprints.hud.ac.uk/id/eprint/8072

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