A key role for transketolase-like 1 in tumor metabolic reprogramming

Abstract

// Santiago Diaz-Moralli 1, 2 , Esther Aguilar 1, 2 , Silvia Marin 1, 2 , Johannes F. Coy 3, 4 , Mieke Dewerchin 5, 6 , Maciek R. Antoniewicz 7 , Oscar Meca-Cortés 8 , Leen Notebaert 5, 6 , Bart Ghesquière 5, 6 , Guy Eelen 5, 6 , Timothy M. Thomson 8 , Peter Carmeliet 5, 6 , Marta Cascante 1, 2 1 Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain 2 Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain 3 Tavargenix GmbH, Frankfurt am Main, Germany 4 Zyagnum AG, Frankfurt am Main, Germany 5 Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, University of Leuven, Leuven, Belgium 6 Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Leuven, Belgium 7 Department of Chemical and Biomolecular Engineering, Metabolic Engineering and Systems Biology Laboratory, University of Delaware, Newark, DE, USA 8 Department of Cell Biology, Institute for Molecular Biology of Barcelona, National Research Council (IBMB-CSIC), Barcelona, Spain Correspondence to: Marta Cascante, email: martacascante@ub.edu Peter Carmeliet, email: peter.carmeliet@vib-kuleuven.be Keywords: tumor metabolism, metabolic reprogramming, transketolase-like 1, lipid metabolism, pentose phosphate pathway Received: March 15, 2016      Accepted: June 13, 2016      Published: July 06, 2016 ABSTRACT Metabolic reprogramming, a crucial cancer hallmark, shifts metabolic pathways such as glycolysis, tricarboxylic acid cycle or lipogenesis, to enable the growth characteristics of cancer cells. Here, we provide evidence that transketolase-like 1 (TKTL1) orchestrates aerobic glycolysis, fatty acid and nucleic acid synthesis, glutamine metabolism, protection against oxidative stress and cell proliferation. Furthermore, silencing of TKTL1 reduced the levels of sphingolipids such as lactosylceramide (a sphingolipid regulating cell survival, proliferation and angiogenesis) and phosphatidylinositol (which activates PI3K/Akt/mTOR signaling). Thus, in addition to its well-known roles in glucose and amino acid metabolism, TKTL1 also regulates lipid metabolism. In conclusion, our study provides unprecedented evidence that TKTL1 plays central roles in major metabolic processes subject to reprogramming in cancer cells and thus identifies TKTL1 as a promising target for new anti-cancer therapies.