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Hypoxia induces a lipogenic cancer cell phenotype via HIF1α-dependent and -independent pathways

Alessandro Valli, _ Miguel Rodriguez, Loukas Moutsianas, Roman Fischer, Vita Fedele, Hong-Lei Huang, Ruud Van Stiphout, Dylan Jones, Michael Mccarthy, Maria Vinaxia, Kaori Igarashi, Maya Sato, Tomoyoshi Soga, Francesca Buffa, James Mccullagh, Oscar Yanes, Adrian Harris, Benedikt Kessler

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Abstract

Alessandro Valli1,2,7, Miguel Rodriguez3,4, Loukas Moutsianas5, Roman Fischer2, Vita Fedele2, Hong-Lei Huang2, Ruud Van Stiphout1, Dylan Jones1, Michael Mccarthy2, Maria Vinaxia3,4, Kaori Igarashi6, Maya Sato6, Tomoyoshi Soga6, Francesca Buffa1, James Mccullagh7, Oscar Yanes3,4, Adrian Harris1,* and Benedikt Kessler2,*

1 Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

2 Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK

3 Centre for Omic Sciences, Rovira i Virgili University, Reus, Spain

4 Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Madrid, Spain

5 The Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, Oxford, UK

6 Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan

7 Mass Spectrometry Research Facility CRL, Department of Chemistry, University of Oxford, Oxford, UK

* equal senior authors

Correspondence:

Alessandro Valli, email:

Keywords: cancer metabolism, fatty acids, HIF1α, HIF2α, hypoxia, Kennedy pathway, lipidomics, PAF

Received: June 01, 2014 Accepted: December 10, 2014 Published: December 11, 2014

Abstract

The biochemistry of cancer cells diverges significantly from normal cells as a result of a comprehensive reprogramming of metabolic pathways. A major factor influencing cancer metabolism is hypoxia, which is mediated by HIF1α and HIF2α. HIF1α represents one of the principal regulators of metabolism and energetic balance in cancer cells through its regulation of glycolysis, glycogen synthesis, Krebs cycle and the pentose phosphate shunt. However, less is known about the role of HIF1α in modulating lipid metabolism. Lipids serve cancer cells to provide molecules acting as oncogenic signals, energetic reserve, precursors for new membrane synthesis and to balance redox biological reactions. To study the role of HIF1α in these processes, we used HCT116 colorectal cancer cells expressing endogenous HIF1α and cells in which the hif1α gene was deleted to characterize HIF1α-dependent and independent effects on hypoxia regulated lipid metabolites. Untargeted metabolomics integrated with proteomics revealed that hypoxia induced many changes in lipids metabolites. Enzymatic steps in fatty acid synthesis and the Kennedy pathway were modified in a HIF1α-dependent fashion. Palmitate, stearate, PLD3 and PAFC16 were regulated in a HIF-independent manner. Our results demonstrate the impact of hypoxia on lipid metabolites, of which a distinct subset is regulated by HIF1α.

Author Information

Alessandro Valli
Primary Contact  _

Miguel Rodriguez

Loukas Moutsianas

Roman Fischer

Vita Fedele

Hong-Lei Huang

Ruud Van Stiphout

Dylan Jones

Michael Mccarthy

Maria Vinaxia

Kaori Igarashi

Maya Sato

Tomoyoshi Soga

Francesca Buffa

James Mccullagh

Oscar Yanes

Adrian Harris

Benedikt Kessler


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