title: S-nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase.
abstract: S-nitrosoglutathione reductase (GSNOR) represents the best-documented denitrosylase implicated in regulating the levels of proteins posttranslationally modified by nitric oxide on cysteine residues by S-nitrosylation. GSNOR controls a diverse array of physiologic functions, including cellular growth and differentiation, inflammation, and metabolism. Chromosomal deletion of GSNOR results in pathologic protein S-nitrosylation that is implicated in human hepatocellular carcinoma (HCC). Here we identify a metabolic hallmark of aberrant S-nitrosylation in HCC and exploit it for therapeutic gain. We find that hepatocyte GSNOR deficiency is characterized by mitochondrial alteration and by marked increases in succinate dehydrogenase (SDH) levels and activity. We find that this depends on the selective S-nitrosylation of Cys(501) in the mitochondrial chaperone TRAP1, which mediates its degradation. As a result, GSNOR-deficient cells and tumors are highly sensitive to SDH inhibition, namely to α-tocopheryl succinate, an SDH-targeting molecule that induced RIP1/PARP1-mediated necroptosis and inhibited tumor growth. Our work provides a specific molecular signature of aberrant S-nitrosylation in HCC, a novel molecular target in SDH, and a first-in-class therapy to treat the disease. Cancer Res; 76(14); 4170-82. ©2016 AACR.
authors.affiliation: Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Rizza
authors.affiliation: Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Costanza
authors.initials: C
authors.lastname: Montagna
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Cardaci
authors.affiliation: Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Maiani
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Di Giacomo
authors.affiliation: Department of Biochemistry and Molecular Biology and the Villum Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Virginia
authors.initials: V
authors.lastname: Sanchez-Quiles
authors.affiliation: Department of Biochemistry and Molecular Biology and the Villum Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Blagoy
authors.initials: B
authors.lastname: Blagoev
authors.affiliation: CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rasola
authors.affiliation: Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Daniela
authors.initials: D
authors.lastname: De Zio
authors.affiliation: Institute for Transformative Molecular Medicine, Case Western Reserve University and Harrington Discovery Institute, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
authors.affiliation: Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark. Department of Biology, University of Rome Tor Vergata, Rome, Italy. IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.affiliation: Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark. Department of Biology, University of Rome Tor Vergata, Rome, Italy. giufil@cancer.dk filomeni@bio.uniroma2.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Filomeni
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000502:physiology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*
chemical_list: D018841:HSP90 Heat-Shock Proteins; C092306:TRAP1 protein, human; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent; D013385:Succinate Dehydrogenase