Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death.

2.50
Hdl Handle:
http://hdl.handle.net/10541/91488
Title:
Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death.
Authors:
Tennant, D A; Frezza, C; MacKenzie, E D; Nguyen, Q D; Zheng, L; Selak, M A; Roberts, Darren L; Dive, Caroline ( 0000-0002-1726-8850 ) ; Watson, D G; Aboagye, E O; Gottlieb, E
Abstract:
Cells exposed to low-oxygen conditions (hypoxia) alter their metabolism to survive. This response, although vital during development and high-altitude survival, is now known to be a major factor in the selection of cells with a transformed metabolic phenotype during tumorigenesis. It is thought that hypoxia-selected cells have increased invasive capacity and resistance to both chemo- and radiotherapies, and therefore represent an attractive target for antitumor therapy. Hypoxia inducible factors (HIFs) are responsible for the majority of gene expression changes under hypoxia, and are themselves controlled by the oxygen-sensing HIF prolyl hydroxylases (PHDs). It was previously shown that mutations in succinate dehydrogenase lead to the inactivation PHDs under normoxic conditions, which can be overcome by treatment with alpha-ketoglutarate derivatives. Given that solid tumors contain large regions of hypoxia, the reactivation of PHDs in these conditions could induce metabolic catastrophe and therefore prove an effective antitumor therapy. In this report we demonstrate that derivatized alpha-ketoglutarate can be used as a strategy for maintaining PHD activity under hypoxia. By increasing intracellular alpha-ketoglutarate and activating PHDs we trigger PHD-dependent reversal of HIF1 activation, and PHD-dependent hypoxic cell death. We also show that derivatized alpha-ketoglutarate can permeate multiple layers of cells, reducing HIF1alpha levels and its target genes in vivo.
Affiliation:
Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, Scotland G61 1BD, UK.
Citation:
Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. 2009, 28 (45):4009-21 Oncogene
Journal:
Oncogene
Issue Date:
12-Nov-2009
URI:
http://hdl.handle.net/10541/91488
DOI:
10.1038/onc.2009.250
PubMed ID:
19718054
Type:
Article
Language:
en
ISSN:
1476-5594
Appears in Collections:
All Paterson Institute for Cancer Research; Clinical and Experimental Pharmacology Group

Full metadata record

DC FieldValue Language
dc.contributor.authorTennant, D Aen
dc.contributor.authorFrezza, Cen
dc.contributor.authorMacKenzie, E Den
dc.contributor.authorNguyen, Q Den
dc.contributor.authorZheng, Len
dc.contributor.authorSelak, M Aen
dc.contributor.authorRoberts, Darren Len
dc.contributor.authorDive, Carolineen
dc.contributor.authorWatson, D Gen
dc.contributor.authorAboagye, E Oen
dc.contributor.authorGottlieb, Een
dc.date.accessioned2010-02-09T14:24:48Z-
dc.date.available2010-02-09T14:24:48Z-
dc.date.issued2009-11-12-
dc.identifier.citationReactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. 2009, 28 (45):4009-21 Oncogeneen
dc.identifier.issn1476-5594-
dc.identifier.pmid19718054-
dc.identifier.doi10.1038/onc.2009.250-
dc.identifier.urihttp://hdl.handle.net/10541/91488-
dc.description.abstractCells exposed to low-oxygen conditions (hypoxia) alter their metabolism to survive. This response, although vital during development and high-altitude survival, is now known to be a major factor in the selection of cells with a transformed metabolic phenotype during tumorigenesis. It is thought that hypoxia-selected cells have increased invasive capacity and resistance to both chemo- and radiotherapies, and therefore represent an attractive target for antitumor therapy. Hypoxia inducible factors (HIFs) are responsible for the majority of gene expression changes under hypoxia, and are themselves controlled by the oxygen-sensing HIF prolyl hydroxylases (PHDs). It was previously shown that mutations in succinate dehydrogenase lead to the inactivation PHDs under normoxic conditions, which can be overcome by treatment with alpha-ketoglutarate derivatives. Given that solid tumors contain large regions of hypoxia, the reactivation of PHDs in these conditions could induce metabolic catastrophe and therefore prove an effective antitumor therapy. In this report we demonstrate that derivatized alpha-ketoglutarate can be used as a strategy for maintaining PHD activity under hypoxia. By increasing intracellular alpha-ketoglutarate and activating PHDs we trigger PHD-dependent reversal of HIF1 activation, and PHD-dependent hypoxic cell death. We also show that derivatized alpha-ketoglutarate can permeate multiple layers of cells, reducing HIF1alpha levels and its target genes in vivo.en
dc.language.isoenen
dc.subjectVon Hippel-Lindau Tumour Suppressor Proteinen
dc.subject.meshAnimals-
dc.subject.meshCell Death-
dc.subject.meshCell Hypoxia-
dc.subject.meshEnzyme Activation-
dc.subject.meshFemale-
dc.subject.meshHCT116 Cells-
dc.subject.meshHumans-
dc.subject.meshHypoxia-Inducible Factor 1-
dc.subject.meshHypoxia-Inducible Factor 1, alpha Subunit-
dc.subject.meshKetoglutaric Acids-
dc.subject.meshMetabolic Networks and Pathways-
dc.subject.meshMice-
dc.subject.meshMice, Inbred BALB C-
dc.subject.meshMice, Nude-
dc.subject.meshOxygen-
dc.subject.meshProcollagen-Proline Dioxygenase-
dc.subject.meshTransfection-
dc.subject.meshVon Hippel-Lindau Tumor Suppressor Protein-
dc.titleReactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK, The Beatson Institute for Cancer Research, Glasgow, Scotland G61 1BD, UK.en
dc.identifier.journalOncogeneen

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