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.
Highlights
Reprogramming of metabolism is necessary for cancer cells to sustain their growth and survival under adverse micro-environmental conditions [1,2,3]
Exposure to 1% O2 tension for 24 hours led to HIF1α accumulation in wild type HCT116 cells, while no HIF1α signal was observed in hif1α-/cells in normoxic or hypoxic conditions
Hypoxia is a hallmark of many human cancers, a consequence of cancer cell proliferation consuming oxygen and aberrant blood vessel development, leading to the local induction of the transcription factors HIF1α and HIF2α [28]
Summary
Reprogramming of metabolism is necessary for cancer cells to sustain their growth and survival under adverse micro-environmental conditions [1,2,3] This involves both catabolic and anabolic processes including glycolysis, glutamine dependent anaplerosis, glycogenolysis, amino acid synthesis, nucleic acid synthesis [4,5,6] and lipid metabolism [7,8,9]. FASN inhibition diminishes cell proliferation, cell viability and reduces in vivo tumor growth [7, 19] This lipogenic phenotype provides substrates allowing cancer cells to synthetize new cell membranes [8], to store energy and to generate molecules involved in the regulation of cell signal transduction and cell motility, such as lipids rafts, blebs and invadopodia [20,21,22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
