title: Inhibition of succinate dehydrogenase by the mitochondrial chaperone TRAP1 has anti-oxidant and anti-apoptotic effects on tumor cells.
abstract: TRAP1 is a mitochondrial chaperone highly expressed in many tumor types; it inhibits respiratory complex II, down-modulating its succinate dehydrogenase (SDH) enzymatic activity. SDH inhibition in turn leads to a pseudohypoxic state caused by succinate-dependent HIF1α stabilization and promotes neoplastic growth. Here we report that TRAP1 inhibition of SDH also shields cells from oxidative insults and from the ensuing lethal opening of the mitochondrial permeability transition pore. This anti-oxidant activity of TRAP1 protects tumor cells from death in conditions of nutrient paucity that mimic those encountered in the neoplasm during the process of malignant accrual, and it is required for in vitro tumorigenic growth. Our findings demonstrate that SDH inhibition by TRAP1 is oncogenic not only by inducing pseudohypoxia, but also by protecting tumor cells from oxidative stress.
authors.affiliation: CNR Neuroscience Institute and Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Guzzo
authors.affiliation: CNR Neuroscience Institute and Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy. Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Sciacovelli
authors.affiliation: CNR Neuroscience Institute and Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.affiliation: CNR Neuroscience Institute and Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rasola
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009369:Neoplasms / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C092306:TRAP1 protein, human; D013385:Succinate Dehydrogenase