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

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    Authors
    Tennant, D A
    Frezza, C
    MacKenzie, E D
    Nguyen, Q D
    Zheng, L
    Selak, M A
    Roberts, Darren L
    Dive, Caroline
    Watson, D G
    Aboagye, E O
    Gottlieb, E
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    Affiliation
    Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, Scotland G61 1BD, UK.
    Issue Date
    2009-11-12
    
    Metadata
    Show full item record
    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.
    Citation
    Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. 2009, 28 (45):4009-21 Oncogene
    Journal
    Oncogene
    URI
    http://hdl.handle.net/10541/91488
    DOI
    10.1038/onc.2009.250
    PubMed ID
    19718054
    Type
    Article
    Language
    en
    ISSN
    1476-5594
    ae974a485f413a2113503eed53cd6c53
    10.1038/onc.2009.250
    Scopus Count
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    All Paterson Institute for Cancer Research
    Clinical and Experimental Pharmacology Group

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