Fatty Acid Uptake and Lipid Storage Induced by HIF-1α Contribute to Cell Growth and Survival after Hypoxia-Reoxygenation
Karim Bensaad,
Elena Favaro,
Caroline A. Lewis,
Barrie Peck,
Simon Lord,
Jennifer M. Collins,
Katherine E. Pinnick,
Simon Wigfield,
Francesca M. Buffa,
Ji-Liang Li,
Qifeng Zhang,
Michael J.O. Wakelam,
Fredrik Karpe,
Almut Schulze,
Adrian L. Harris
Affiliations
Karim Bensaad
CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK; Corresponding author
Elena Favaro
CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
Caroline A. Lewis
Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
Barrie Peck
Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
Simon Lord
CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
Jennifer M. Collins
Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK
Katherine E. Pinnick
Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK
Simon Wigfield
CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
Francesca M. Buffa
CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
Ji-Liang Li
CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
Qifeng Zhang
The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Michael J.O. Wakelam
The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Fredrik Karpe
Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK; NIHR Oxford Biomedical Research Centre, OUH Trust, Churchill Hospital, Oxford OX3 7LF, UK
Almut Schulze
Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK; Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, Am Hubland, 97074 Würzburg, Germany
Adrian L. Harris
CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
Summary: An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via β-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo. : Bensaad et al. now show that FABP3 and FABP7 are induced by HIF-1α and lead to a significant lipid droplet (LD) accumulation in hypoxia. In hypoxia-reoxygenation, ATP production occurs via fatty acid β-oxidation or glycogen degradation in a cell-type-dependent manner, while inhibition of LD formation increases ROS toxicity and decreases cell survival in vitro and strongly impairs tumorigenesis in vivo.
