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

Dieter M Matlac1, Katerina Hadrava Vanova2,3, Nicole Bechmann4

  • 1Neuroendocrine Oncology and Metabolism, Medical Department I, Center of Brain, Behavior, and Metabolism, University Medical Center Schleswig-Holstein Lübeck, Lübeck, Germany.

Frontiers in Endocrinology
|March 29, 2021
PubMed

Insights

Succinate accumulation due to SDHx mutations fuels paraganglioma and pheochromocytoma growth via SUCNR1 signaling. Inhibiting this pathway offers a potential therapeutic strategy for these rare tumors.

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • Paragangliomas and pheochromocytomas (PPGLs) are tumors causing severe catecholamine-related issues.
  • Succinate dehydrogenase subunit (SDHx) mutations increase recurrence and metastasis risk in PPGLs, necessitating new treatments.
  • Elevated succinate receptor 1 (SUCNR1) was previously observed in SDHx-mutated PPGLs.

Purpose of the Study:

  • To investigate the role of autocrine SUCNR1 stimulation in the pathogenesis of SDHx mutation-derived PPGLs.
  • To explore SUCNR1 as a potential therapeutic target for SDHx-mutated PPGLs.

Main Methods:

  • Confirmed elevated SUCNR1 expression in SDHx PPGLs and SDHB-knockout cells.
  • Assessed the effect of succinate on SUCNR1-transfected cells, including viability and ERK pathway signaling.
  • Tested candidate SUCNR1 inhibitors for their ability to reverse succinate-induced proliferation.

Main Results:

  • SDHx PPGLs exhibit increased SUCNR1 expression.
  • Succinate significantly enhances cell viability and ERK pathway signaling in SUCNR1-expressing cells.
  • SUCNR1 inhibitors effectively counteract succinate's proliferative effects.

Conclusions:

  • Succinate acts as an oncometabolite in SDHx PPGLs by promoting tumor growth through SUCNR1.
  • Targeting the SUCNR1 pathway represents a promising therapeutic avenue for SDHx-mutated PPGLs.
Keywords:
SDHB geneSUCNR1 (GPR91)paragangliomasuccinatesuccinate receptor 1

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