title: The multikinase inhibitor Sorafenib enhances glycolysis and synergizes with glycolysis blockade for cancer cell killing.
abstract: Although the only effective drug against primary hepatocarcinoma, the multikinase inhibitor Sorafenib (SFB) usually fails to eradicate liver cancer. Since SFB targets mitochondria, cell metabolic reprogramming may underlie intrinsic tumor resistance. To characterize cancer cell metabolic response to SFB, we measured oxygen consumption, generation of reactive oxygen species (ROS) and ATP content in rat LCSC (Liver Cancer Stem Cells) -2 cells exposed to the drug. Genome wide analysis of gene expression was performed by Affymetrix technology. SFB cytotoxicity was evaluated by multiple assays in the presence or absence of metabolic inhibitors, or in cells genetically depleted of mitochondria. We found that low concentrations (2.5-5 μM) of SFB had a relatively modest effect on LCSC-2 or 293 T cell growth, but damaged mitochondria and increased intracellular ROS. Gene expression profiling of SFB-treated cells was consistent with a shift toward aerobic glycolysis and, accordingly, SFB cytotoxicity was dramatically increased by glucose withdrawal or the glycolytic inhibitor 2-DG. Under metabolic stress, activation of the AMP dependent Protein Kinase (AMPK), but not ROS blockade, protected cells from death. We conclude that mitochondrial damage and ROS drive cell killing by SFB, while glycolytic cell reprogramming may represent a resistance strategy potentially targetable by combination therapies.
authors.affiliation: Institute of Internal Medicine and Gastroenterology, Catholic University of the Sacred Heart School of Medicine.
authors.forename: Valentina
authors.initials: V
authors.lastname: Tesori
authors.affiliation: Institute of Internal Medicine and Gastroenterology, Catholic University of the Sacred Heart School of Medicine.
authors.forename: Anna Chiara
authors.initials: AC
authors.lastname: Piscaglia
authors.affiliation: Institute of General Pathology, Laboratory of Cell Signaling, Catholic University of the Sacred Heart School of Medicine.
authors.forename: Daniela
authors.initials: D
authors.lastname: Samengo
authors.affiliation: Institute of Human Anatomy and Cell Biology, Catholic University of the Sacred Heart School of Medicine.
authors.forename: Marta
authors.initials: M
authors.lastname: Barba
authors.affiliation: Institute of Human Anatomy and Cell Biology, Catholic University of the Sacred Heart School of Medicine.
authors.forename: Camilla
authors.initials: C
authors.lastname: Bernardini
authors.affiliation: Institute of Biochemistry and Clinical Biochemistry, Catholic University of the sacred Heart School of Medicine.
authors.forename: Roberto
authors.initials: R
authors.lastname: Scatena
authors.affiliation: Institute of Biochemistry and Clinical Biochemistry, Catholic University of the sacred Heart School of Medicine.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pontoglio
authors.affiliation: Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Castellini
authors.affiliation: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, Geert Grooteplein 10, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Institute of Biomedical Technology &Tampere University Hospital, Pirkanmaa Hospital District, University of Tampere, FI-33014, Finland.
authors.forename: Johannes N
authors.initials: JN
authors.lastname: Spelbrink
authors.affiliation: Institute of Physics, Catholic University of the Sacred Heart School of Medicine.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Maulucci
authors.affiliation: Institute of Internal Medicine and Gastroenterology, Catholic University of the Sacred Heart School of Medicine.
authors.forename: Maria Ausiliatrice
authors.initials: MA
authors.lastname: Puglisi
authors.affiliation: Institute of General Pathology, Laboratory of Cell Signaling, Catholic University of the Sacred Heart School of Medicine.
authors.forename: Giovambattista
authors.initials: G
authors.lastname: Pani
authors.affiliation: Institute of Internal Medicine and Gastroenterology, Catholic University of the Sacred Heart School of Medicine.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gasbarrini
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D009536:Niacinamide; D003847:Deoxyglucose; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases