S-nitrosylation of the mitochondrial chaperone TRAP1 sensitizes hepatocellular carcinoma cells to inhibitors of succinate dehydrogenase

Salvatore Rizza, Costanza Montagna, Simone Cardaci, Emiliano Maiani, Giuseppina Di Giacomo, Virginia Sanchez-Quiles, Blagoy Blagoev, Andrea Rasola, Daniela De Zio, Jonathan S Stamler, Francesco Cecconi, Giuseppe Filomeni

Research output: Contribution to journalJournal articleResearchpeer-review


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); 1-13. ©2016 AACR.

Original languageEnglish
JournalCancer Research
Issue number14
Pages (from-to)4170-4182
Publication statusPublished - 2016


  • Aldehyde Oxidoreductases/physiology
  • Animals
  • Carcinoma, Hepatocellular/drug therapy
  • HSP90 Heat-Shock Proteins/metabolism
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms/drug therapy
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria/metabolism
  • Oxidative Stress
  • Succinate Dehydrogenase/antagonists & inhibitors


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