title: Sorafenib-induced mitochondrial complex I inactivation and cell death in human neuroblastoma cells.
abstract: Sorafenib is a multikinase inhibitor that is approved for use against renal cell and hepatocellular carcinoma. We found that sorafenib potently induced cell death in human neuroblastoma cells. To understand the molecular basis of sorafenib-mediated cell death in human SH-SY5Y cells, we performed a temporal quantitative proteome analysis. The results showed significant quantitative changes of 193 unique proteins. Bioinformatics-assisted pathway analysis of the regulated proteins revealed that mitochondrial proteins, especially components of the electron transport chain and the mitochondrial ribosomes, were significantly affected upon exposure to sorafenib. The observed down-regulation of the respiratory chain complex I (NADH dehydrogenase) was accompanied with loss of mitochondrial transmembrane potential (Δψm) and complete impairment of complex I enzyme activity. The destabilization of complex I subunits was consistent, rapid, and independent of caspase activation as well as Bcl-2 overexpression. This study provides an overview of the molecular machinery driving sorafenib-mediated cell death in neuroblastoma cells and suggests that sorafenib could be a potential therapeutic drug for the treatment of neuroblastoma.
authors.affiliation: The Biotechnology Centre of Oslo, University of Oslo , P.O. Box 1125 Blindern, 0317 Oslo, Norway.
authors.forename: Vibeke Hervik
authors.initials: VH
authors.lastname: Bull
authors.forename: Krishnaraj
authors.initials: K
authors.lastname: Rajalingam
authors.forename: Bernd
authors.initials: B
authors.lastname: Thiede
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001557:Benzenesulfonates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D060066:Protein Interaction Maps; D059748:Proteolysis / Q000187:drug effects; D020543:Proteome / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D000077157:Sorafenib; D013482:Superoxide Dismutase / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001557:Benzenesulfonates; D045304:Cytochromes c; D009245:NADH Dehydrogenase; D009536:Niacinamide; D010671:Phenylurea Compounds; D020543:Proteome; D011725:Pyridines; D017382:Reactive Oxygen Species; D000077157:Sorafenib; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2