Reference : The role of HIF-1 in oncostatin M-dependent metabolic reprogramming of hepatic cells.
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/10993/27303
The role of HIF-1 in oncostatin M-dependent metabolic reprogramming of hepatic cells.
English
Battello, Nadia mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Zimmer, Andreas David mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Goebel, Carole [> >]
Dong, Xiangyi mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Behrmann, Iris mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Haan, Claude mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Hiller, Karsten mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Wegner, Andre [> >]
2016
Cancer & metabolism
4
3
Yes (verified by ORBilu)
International
2049-3002
2049-3002
England
[en] Hypoxia-inducible factor ; Inflammation ; Oncostatin M ; Pyruvate dehydrogenase complex ; Pyruvate dehydrogenase kinase ; Stable isotope labeling experiments
[en] BACKGROUND: Hypoxia and inflammation have been identified as hallmarks of cancer. A majority of hepatocellular carcinomas are preceded by hepatitis B- or C-related chronic infections suggesting that liver cancer development is promoted by an inflammatory microenvironment. The inflammatory cytokine oncostatin M (OSM) was shown to induce the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) under normoxic conditions in hepatocytes and hepatoma cells. HIF-1 alpha is known to orchestrate the expression of numerous genes, many of which code for metabolic enzymes that play key roles in the adaptation of cellular metabolism to low oxygen tension. RESULTS: Here, we show that OSM-induced upregulation of HIF-1 alpha reprograms cellular metabolism in three clones of the human hepatocyte cell line PH5CH (PH5CH1, PH5CH7, and PH5CH8) towards a hypoxia-like metabolic phenotype but has no significant effect on cellular metabolism of HepG2 and JHH-4 hepatoma cells. Although we observed only minor changes in glucose uptake and lactate secretion in PH5CH8 upon OSM treatment, we identified more pronounced changes in intracellular fluxes based on stable isotope labeling experiments. In particular, glucose oxidation in the tricarboxylic acid (TCA) cycle is reduced through pyruvate dehydrogenase kinase 1 (PDK1)-mediated inhibition of the pyruvate dehydrogenase complex, thereby reducing the oxidative TCA cycle flux. As a result of the impaired mitochondrial glucose and glutamine oxidation, the reductive isocitrate dehydrogenase flux was increased. CONCLUSIONS: We provide evidence that connects the inflammatory mediator OSM to a hypoxia-like metabolic phenotype. In the human hepatocyte cell line PH5CH, OSM-mediated upregulation of HIF-1 alpha and PDK1 can induce hypoxia-like metabolic changes, although to a lesser extent than hypoxia itself. Since PDK1 is overexpressed in several cancers, it might provide a causal link between chronic inflammation and malignant cellular transformation.
Luxembourg Centre for Systems Biomedicine (LCSB): Metabolomics (Hiller Group)
http://hdl.handle.net/10993/27303
10.1186/s40170-016-0141-0

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