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

Salvatore Rizza, C. 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 journalArticlepeer-review

Abstract

S-nitrosoglutathione reductase (GSNOR) represents the bestdocumented 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, GSNORdeficient cells and tumors are highly sensitive to SDH inhibition, namely to a-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.

Original languageEnglish
Pages (from-to)4170-4182
Number of pages13
JournalCancer Research
Volume76
Issue number14
DOIs
Publication statusPublished - Jul 15 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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