Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death.
AuthorsTennant, D A
MacKenzie, E D
Nguyen, Q D
Selak, M A
Roberts, Darren L
Watson, D G
Aboagye, E O
AffiliationCancer Research UK, The Beatson Institute for Cancer Research, Glasgow, Scotland G61 1BD, UK.
MetadataShow full item record
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.
CitationReactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. 2009, 28 (45):4009-21 Oncogene
- HIF prolyl hydroxylase-3 mediates alpha-ketoglutarate-induced apoptosis and tumor suppression.
- Authors: Tennant DA, Gottlieb E
- Issue date: 2010 Aug
- Prolyl hydroxylase 2 dependent and Von-Hippel-Lindau independent degradation of Hypoxia-inducible factor 1 and 2 alpha by selenium in clear cell renal cell carcinoma leads to tumor growth inhibition.
- Authors: Chintala S, Najrana T, Toth K, Cao S, Durrani FA, Pili R, Rustum YM
- Issue date: 2012 Jul 17
- Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases.
- Authors: Chowdhury R, McDonough MA, Mecinović J, Loenarz C, Flashman E, Hewitson KS, Domene C, Schofield CJ
- Issue date: 2009 Jul 15
- The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity.
- Authors: Foxler DE, Bridge KS, James V, Webb TM, Mee M, Wong SC, Feng Y, Constantin-Teodosiu D, Petursdottir TE, Bjornsson J, Ingvarsson S, Ratcliffe PJ, Longmore GD, Sharp TV
- Issue date: 2012 Jan 29
- PHDs overactivation during chronic hypoxia "desensitizes" HIFalpha and protects cells from necrosis.
- Authors: Ginouvès A, Ilc K, Macías N, Pouysségur J, Berra E
- Issue date: 2008 Mar 25