title: NMR metabolomics highlights sphingosine kinase-1 as a new molecular switch in the orchestration of aberrant metabolic phenotype in cancer cells.
abstract: Strong experimental evidence in animal and cellular models supports a pivotal role of sphingosine kinase-1 (SK1) in oncogenesis. In many human cancers, SK1 levels are upregulated and these increases are linked to poor prognosis in patients. Here, by employing untargeted NMR-based metabolomic profiling combined with functional validations, we report the crucial role of SK1 in the metabolic shift known as the Warburg effect in A2780 ovarian cancer cells. Indeed, expression of SK1 induced a high glycolytic rate, characterized by increased levels of lactate along with increased expression of the proton/monocarboxylate symporter MCT1, and decreased oxidative metabolism, associated with the accumulation of intermediates of the tricarboxylic acid cycle and reduction in CO2production. Additionally, SK1-expressing cells displayed a significant increase in glucose uptake paralleled by GLUT3 transporter upregulation. The role of SK1 is not limited to the induction of aerobic glycolysis, affecting metabolic pathways that appear to support the biosynthesis of macromolecules. These findings highlight the role of SK1 signaling axis in cancer metabolic reprogramming, pointing out innovative strategies for cancer therapies.
authors.affiliation: Department of Biomedical, Clinical and Experimental Sciences, University of Florence, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bernacchioni
authors.affiliation: CERM and Department of Chemistry, University of Florence, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghini
authors.affiliation: Department of Biomedical, Clinical and Experimental Sciences, University of Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cencetti
authors.affiliation: Department of Toxicology, Faculty of Mathematics and Natural Science, Institute of Nutritional Science, University of Potsdam, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Japtok
authors.affiliation: Department of Biomedical, Clinical and Experimental Sciences, University of Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Donati
authors.affiliation: Department of Biomedical, Clinical and Experimental Sciences, University of Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Bruni
authors.affiliation: CERM and Department of Chemistry, University of Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Turano
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005947:Glucose / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000032:analysis / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D055432:Metabolomics / Q000379:methods*; D008928:Mitochondria / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000494:pharmacology*; D011379:Prognosis; D014233:Tricarboxylic Acids / Q000378:metabolism; D015854:Up-Regulation; D000099157:Sphingosine Kinase
chemical_list: D002245:Carbon Dioxide; D018797:Cell Cycle Proteins; D005947:Glucose; D051274:Glucose Transporter Type 3; D019344:Lactic Acid; D015513:Oncogene Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D014233:Tricarboxylic Acids; D000099157:Sphingosine Kinase; C115081:MCTS1 protein, human; C495687:SLC2A3 protein, human
keywords: NMR-based metabolomics; Warburg effect; ovarian cancer; sphingosine kinase-1