Document Detail


Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death.
MedLine Citation:
PMID:  19718054     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-08-31
Journal Detail:
Title:  Oncogene     Volume:  28     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-11-12     Completed Date:  2009-12-04     Revised Date:  2014-03-17    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  4009-21     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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
Hypoxia-Inducible Factor-Proline Dioxygenases
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:
10337//Cancer Research UK; MC_U120081322//Medical Research Council; //Cancer Research UK
Chemical
Reg. No./Substance:
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; EC 1.14.11.2/EGLN1 protein, human; EC 1.14.11.2/Procollagen-Proline Dioxygenase; EC 1.14.11.29/Hypoxia-Inducible Factor-Proline Dioxygenases; EC 6.3.2.19/VHL protein, human; EC 6.3.2.19/Von Hippel-Lindau Tumor Suppressor Protein; S88TT14065/Oxygen

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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