Elevated endogenous SDHA drives pathological metabolism in highly metastatic uveal melanoma

Chandrani Chattopadhyay, Junna Oba, Jason Roszik, Joseph R. Marszalek, Ken Chen, Yuan Qi, Karina Eterovic, A. Gordon Robertson, Jared K. Burks, Tara A. McCannel, Elizabeth A. Grimm, Scott E. Woodman

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

PURPOSE. Metastatic uveal melanoma (UM) has a very poor prognosis and no effective therapy. Despite remarkable advances in treatment of cutaneous melanoma, UM remains recalcitrant to chemotherapy, small-molecule kinase inhibitors, and immune-based therapy. METHODS. We assessed two sets of oxidative phosphorylation (OxPhos) genes within 9858 tumors across 31 cancer types. An OxPhos inhibitor was used to characterize differential metabolic programming of highly metastatic monosomy 3 (M3) UM. Seahorse analysis and global metabolomics profiling were done to identify metabolic vulnerabilities. Analyses of UM TCGA data set were performed to determine expressions of key OxPhos effectors in M3 and non-M3 UM. We used targeted knockdown of succinate dehydrogenase A (SDHA) to determine the role of SDHA in M3 UM in conferring resistance to OxPhos inhibition. RESULTS. We identified UM to have among the highest median OxPhos levels and showed that M3 UM exhibits a distinct metabolic profile. M3 UM shows markedly low succinate levels and has highly increased levels of SDHA, the enzyme that couples the tricarboxylic acid cycle with OxPhos by oxidizing (lowering) succinate. We showed that SDHA-high M3 UM have elevated expression of key OxPhos molecules, exhibit abundant mitochondrial reserve respiratory capacity, and are resistant to OxPhos antagonism, which can be reversed by SDHA knockdown. CONCLUSIONS. Our study has identified a critical metabolic program within poor prognostic M3 UM. In addition to the heightened mitochondrial functional capacity due to elevated SDHA, M3 UM SDHA-high mediate resistance to therapy that is reversible with targeted treatment.

Original languageEnglish
Pages (from-to)4187-4195
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume60
Issue number13
DOIs
Publication statusPublished - 2019 Oct 1
Externally publishedYes

Keywords

  • Mitochondrial metabolism
  • Monosomy 3
  • OxPhos
  • SDHA
  • Uveal melanoma

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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