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Sci Rep. 2017 Oct 2;7(1):12486. doi: 10.1038/s41598-017-12837-y.

Role of the Transforming Growth Factor-β in regulating hepatocellular carcinoma oxidative metabolism.

Author information

1
Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
2
Department of Physiological Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
3
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
4
Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
5
Metabolomics Platform, Department of Electronic Engineering (DEEEA), Universitat Rovira i Virgili, Tarragona, Spain.
6
National Institute of Gastroenterology IRCCS "S. De Bellis", Castellana Grotte Bari, Italy.
7
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
8
Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain. ifabregat@idibell.cat.
9
Department of Physiological Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain. ifabregat@idibell.cat.

Abstract

Transforming Growth Factor beta (TGF-β) induces tumor cell migration and invasion. However, its role in inducing metabolic reprogramming is poorly understood. Here we analyzed the metabolic profile of hepatocellular carcinoma (HCC) cells that show differences in TGF-β expression. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR), metabolomics and transcriptomics were performed. Results indicated that the switch from an epithelial to a mesenchymal/migratory phenotype in HCC cells is characterized by reduced mitochondrial respiration, without significant differences in glycolytic activity. Concomitantly, enhanced glutamine anaplerosis and biosynthetic use of TCA metabolites were proved through analysis of metabolite levels, as well as metabolic fluxes from U-13C6-Glucose and U-13C5-Glutamine. This correlated with increase in glutaminase 1 (GLS1) expression, whose inhibition reduced cell migration. Experiments where TGF-β function was activated with extracellular TGF-β1 or inhibited through TGF-β receptor I silencing showed that TGF-β induces a switch from oxidative metabolism, coincident with a decrease in OCR and the upregulation of glutamine transporter Solute Carrier Family 7 Member 5 (SLC7A5) and GLS1. TGF-β also regulated the expression of key genes involved in the flux of glycolytic intermediates and fatty acid metabolism. Together, these results indicate that autocrine activation of the TGF-β pathway regulates oxidative metabolism in HCC cells.

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