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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31 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1920-1941
Number of pages22
JournalOncotarget
Volume6
Issue number4
DOIs
Publication statusPublished - 2015 Jan 1

Keywords

  • Cancer metabolism
  • Fatty acids
  • HIF1α
  • HIF2α
  • Hypoxia
  • Kennedy pathway
  • Lipidomics
  • PAF

ASJC Scopus subject areas

  • Oncology

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    Valli, A., Rodriguez, M., Moutsianas, L., Fischer, R., Fedele, V., Huang, H. L., Van Stiphout, R., Jones, D., Mccarthy, M., Vinaxia, M., Igarashi, K., Sato, M., Soga, T., Buffa, F., Mccullagh, J., Yanes, O., Harris, A., & Kessler, B. (2015). Hypoxia induces a lipogenic cancer cell phenotype via HIF1α-dependent and -independent pathways. Oncotarget, 6(4), 1920-1941. https://doi.org/10.18632/oncotarget.3058