The multikinase inhibitor Sorafenib enhances glycolysis and synergizes with glycolysis blockade for cancer cell killing
| Autor: | Laura Castellini, Alessandro Pontoglio, Anna Chiara Piscaglia, Marta Barba, Johannes N. Spelbrink, Roberto Scatena, Giovambattista Pani, Camilla Bernardini, Daniela Maria Samengo, Giuseppe Maulucci, Maria Ausiliatrice Puglisi, Valentina Tesori, Antonio Gasbarrini |
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| Přispěvatelé: | BioMediTech - BioMediTech, University of Tampere |
| Rok vydání: | 2015 |
| Předmět: |
cancer stem cells
Cell Mitochondrion AMP-Activated Protein Kinases 0302 clinical medicine Tumor Metabolism AMP-activated protein kinase Lääketieteen bioteknologia - Medical biotechnology 0303 health sciences Multidisciplinary TOR Serine-Threonine Kinases Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] Sorafenib 2 deoxy glucose synthetic letahlity 3. Good health Mitochondria Cell killing medicine.anatomical_structure Biochemistry 030220 oncology & carcinogenesis Glycolysis Signal Transduction Niacinamide Cell Survival Settore MED/12 - GASTROENTEROLOGIA Cell Respiration Antineoplastic Agents Biology Deoxyglucose Article 03 medical and health sciences Settore MED/04 - PATOLOGIA GENERALE Cancer stem cell Syöpätaudit - Cancers Cell Line Tumor medicine Autophagy Animals Protein Kinase Inhibitors 030304 developmental biology Cell growth Phenylurea Compounds Rats hepatocarcinoma Anaerobic glycolysis Cancer cell biology.protein Cancer research Energy Metabolism Reactive Oxygen Species |
| Zdroj: | Scientific Reports, 5 Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Contains fulltext : 154217.pdf (Publisher’s version ) (Open Access) 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 muM) 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. |
| Databáze: | OpenAIRE |
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