Succinate Mediates Tumorigenic Effects via Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Dieter M. Matlac - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck (Author)
  • Katerina Hadrava Vanova - , Czech Academy of Sciences, National Institutes of Health (NIH) (Author)
  • Nicole Bechmann - , Institute of Clinical Chemistry and Laboratory Medicine (Author)
  • Susan Richter - , Institute of Clinical Chemistry and Laboratory Medicine (Author)
  • Julica Folberth - , University of Lübeck (Author)
  • Hans K. Ghayee - , University of Florida (Author)
  • Guang Bo Ge - , Shanghai University of Traditional Chinese Medicine (Author)
  • Luma Abunimer - , National Institutes of Health (NIH) (Author)
  • Robert Wesley - (Author)
  • Redouane Aherrahrou - , University of Lübeck, University of Virginia (Author)
  • Margo Dona - , Radboud University Nijmegen (Author)
  • Ángel M. Martínez-Montes - , Instituto de Salud Carlos III (Author)
  • Bruna Calsina - , Instituto de Salud Carlos III (Author)
  • Maria J. Merino - , National Institutes of Health (NIH) (Author)
  • Markus Schwaninger - , University of Lübeck (Author)
  • Peter M.T. Deen - , Radboud University Nijmegen (Author)
  • Zhengping Zhuang - , National Institutes of Health (NIH) (Author)
  • Jiri Neuzil - , Czech Academy of Sciences, Griffith University Queensland (Author)
  • Karel Pacak - , National Institutes of Health (NIH) (Author)
  • Hendrik Lehnert - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck (Author)
  • Stephanie M.J. Fliedner - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck (Author)

Abstract

Paragangliomas and pheochromocytomas (PPGLs) are chromaffin tumors associated with severe catecholamine-induced morbidities. Surgical removal is often curative. However, complete resection may not be an option for patients with succinate dehydrogenase subunit A-D (SDHx) mutations. SDHx mutations are associated with a high risk for multiple recurrent, and metastatic PPGLs. Treatment options in these cases are limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is thus urgently needed. Previously, we showed elevated expression of succinate receptor 1 (SUCNR1) in SDHB PPGLs and SDHD head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to SDHx mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of SDHx mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in SDHx PPGLs and after SDHB knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of SUCNR1-transfected PC12 and ERK pathway signaling compared to control cells. Candidate SUCNR1 inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in SDHx PPGLs, providing a growth advantage via SUCNR1.

Details

Original languageEnglish
Article number589451
JournalFrontiers in endocrinology
Volume12
Publication statusPublished - 12 Mar 2021
Peer-reviewedYes

External IDs

ORCID /0000-0002-6932-333X/work/142239666
ORCID /0000-0002-3549-2477/work/142244894

Keywords

Sustainable Development Goals

Keywords

  • paraganglioma, SDHB gene, succinate, succinate receptor 1, SUCNR1 (GPR91)