title: A protective role for HIF-1 in response to redox manipulation and glucose deprivation: implications for tumorigenesis.
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-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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Manchester, M13 9PL, UK. kaye.williams@man.ac.uk
authors.forename: Kaye J
authors.initials: KJ
authors.lastname: Williams
authors.forename: Brian A
authors.initials: BA
authors.lastname: Telfer
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Airley
authors.forename: Hans P W
authors.initials: HP
authors.lastname: Peters
authors.forename: Mary R
authors.initials: MR
authors.lastname: Sheridan
authors.forename: Albert J
authors.initials: AJ
authors.lastname: van der Kogel
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
mesh_terms: D000818:Animals; D016466:CHO Cells; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D006801:Humans; D007003:Hypoglycemia / Q000503:physiopathology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008819:Mice, Nude; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000235:genetics; D016296:Mutagenesis; D009389:Neovascularization, Pathologic / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D014157:Transcription Factors / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; C495677:SLC2A1 protein, human; C495678:Slc2a1 protein, mouse; D014157:Transcription Factors; D005947:Glucose