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

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.

• Authors: Dieter M Matlac, Katerina Hadrava Vanova, Nicole Bechmann, Susan Richter, Julica Folberth, Hans K Ghayee, Guang-Bo Ge, Luma Abunimer, Robert Wesley, Redouane Aherrahrou, Margo Dona, Ángel M Martínez-Montes, Bruna Calsina, Maria J Merino, Markus Schwaninger, Peter M T Deen, Zhengping Zhuang, Jiri Neuzil, Karel Pacak, Hendrik Lehnert, Stephanie M J Fliedner
• Journal: Frontiers in endocrinology (Front Endocrinol (Lausanne)) Vol. 12 Pg. 589451 ( 2021) ISSN: 1664-2392 [Print] Switzerland
• PMID: 33776908 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Matlac, Hadrava Vanova, Bechmann, Richter, Folberth, Ghayee, Ge, Abunimer, Wesley, Aherrahrou, Dona, Martínez-Montes, Calsina, Merino, Schwaninger, Deen, Zhuang, Neuzil, Pacak, Lehnert and Fliedner.

Chemical References

• Protein Subunits
• Receptors, G-Protein-Coupled
• SDHD protein, human
• SUCNR1 protein, human
• Succinic Acid
• Succinate Dehydrogenase

Topics

• Animals
• Humans
• Mice
• Mutation
• Paraganglioma (drug therapy, enzymology, genetics, metabolism)
• Pheochromocytoma (drug therapy, enzymology, genetics, metabolism)
• Protein Subunits (genetics, metabolism)
• Rats
• Receptors, G-Protein-Coupled (antagonists & inhibitors, genetics, metabolism)
• Succinate Dehydrogenase (deficiency, genetics)
• Succinic Acid (metabolism)