1. S-nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase
- Author
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Virginia Sanchez-Quiles, Giuseppina Di Giacomo, Salvatore Rizza, Andrea Rasola, Emiliano Maiani, Giuseppe Filomeni, Daniela De Zio, Simone Cardaci, Jonathan S. Stamler, Blagoy Blagoev, Costanza Montagna, and Francesco Cecconi
- Subjects
0301 basic medicine ,Succinate Dehydrogenase/antagonists & inhibitors ,Cancer Research ,Carcinoma, Hepatocellular ,Oncology ,Necroptosis ,Inflammation ,Reductase ,Carcinoma, Hepatocellular/drug therapy ,Liver Neoplasms/drug therapy ,Nitric oxide ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Mitochondria/metabolism ,medicine ,Animals ,Humans ,HSP90 Heat-Shock Proteins ,Settore BIO/10 ,biology ,Cell growth ,Succinate dehydrogenase ,Liver Neoplasms ,Hep G2 Cells ,S-Nitrosylation ,Aldehyde Oxidoreductases ,Molecular biology ,Mitochondria ,Succinate Dehydrogenase ,Mice, Inbred C57BL ,Oxidative Stress ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Chaperone (protein) ,Cancer research ,biology.protein ,HSP90 Heat-Shock Proteins/metabolism ,medicine.symptom ,Aldehyde Oxidoreductases/physiology - 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 Cys501 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.
- Published
- 2016