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

Oncogene volume 28, pages 4009–4021 (2009)Cite this article

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 α-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 α-ketoglutarate can be used as a strategy for maintaining PHD activity under hypoxia. By increasing intracellular α-ketoglutarate and activating PHDs we trigger PHD-dependent reversal of HIF1 activation, and PHD-dependent hypoxic cell death. We also show that derivatized α-ketoglutarate can permeate multiple layers of cells, reducing HIF1α levels and its target genes in vivo.

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Acknowledgements

This work was supported by Cancer Research UK and the Association for International Cancer Research. We thank Tom Hamilton and Derek Miller for their invaluable assistance with the in vivo work, Colin Nixon and Mairi Macdonald for helping with the histology, Margaret O’Prey for help with the microscopy, Celeste Simon for generously providing us with the HIF1α-expressing plasmid and Ayala King for her excellent editorial work.

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Author notes

  1. M A Selak

    Present address: 5Current address: Children's Hospital of Philadelphia Research Institute, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA USA.,

Authors and Affiliations

  1. Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, UK

    D A Tennant, C Frezza, E D MacKenzie, M A Selak & E Gottlieb

  2. Comprehensive Cancer Imaging Center, Faculty of Medicine, Hammersmith Hospital, Imperial College London, London, UK

    Q D Nguyen & E O Aboagye

  3. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK

    L Zheng & D G Watson

  4. Cancer Research UK, Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK

    D L Roberts & C Dive

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  1. D A Tennant
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Correspondence to E Gottlieb.

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Tennant, D., Frezza, C., MacKenzie, E. et al. Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. Oncogene 28, 4009–4021 (2009). https://doi.org/10.1038/onc.2009.250

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