Hypoxia induces a lipogenic cancer cell phenotype via HIF1a-dependent and -independent pathways

Journal article

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 HIF1a and HIF2a. HIF1a 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 HIF1a 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 HIF1a in these processes, we used HCT116 colorectal cancer cells expressing endogenous HIF1a and cells in which the hif1a gene was deleted to characterize HIF1a-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 HIF1a-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 HIF1a.

Authors: Valli, A; Rodriguez, M; Moutsianas, L; Fischer, R; Fedele, V

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Impact Journals
• Journal: Oncotarget
• Volume: 6
• Issue: 4
• Pages: 1920-1941
• Publication date: 2014-12-11
• Acceptance date: 2014-12-10
• DOI: 10.18632/oncotarget.3058
• EISSN: 1949-2553
• ISSN: 1949-2553
• Language: English
• Keywords: genomics; lipid metabolism; cell line, tumor; aged; blotting, western; humans; hypoxia-inducible factor 1, alpha subunit; male; metabolomics; female; basic helix-loop-helix transcription factors; HCT116 cells; middle aged; acetyl-CoA C-acyltransferase; fatty acids; colorectal neoplasms; lipids; platelet activating factor; signal transduction; RNA interference; SBTMR; proteomics; cell hypoxia; acetyl-CoA carboxylase