| Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. | |
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MedLine Citation:
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PMID: 19718054 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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D A Tennant; C Frezza; E D MacKenzie; Q D Nguyen; L Zheng; M A Selak; D L Roberts; C Dive; D G Watson; E O Aboagye; E Gottlieb |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-08-31 |
Journal Detail:
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Title: Oncogene Volume: 28 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2009 Nov |
Date Detail:
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Created Date: 2009-11-12 Completed Date: 2009-12-04 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 4009-21 Citation Subset: IM |
Affiliation:
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Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, Scotland G61 1BD, UK. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Death / physiology Cell Hypoxia / physiology Enzyme Activation Female HCT116 Cells Humans Hypoxia-Inducible Factor 1 / genetics, metabolism* Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Ketoglutaric Acids / metabolism, pharmacology Metabolic Networks and Pathways Mice Mice, Inbred BALB C Mice, Nude Oxygen / metabolism Procollagen-Proline Dioxygenase / metabolism* Transfection Von Hippel-Lindau Tumor Suppressor Protein / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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//Cancer Research UK |
| Chemical | |
Reg. No./Substance:
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0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Ketoglutaric Acids; 328-50-7/alpha-ketoglutaric acid; 7782-44-7/Oxygen; EC 1.14.11.2/EGLN1 protein, human; EC 1.14.11.2/Procollagen-Proline Dioxygenase; EC 6.3.2.19/VHL protein, human; EC 6.3.2.19/Von Hippel-Lindau Tumor Suppressor Protein |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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