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.
Highlights
Paragangliomas (PGLs) are catecholamine-producing chromaffin tumors of the autonomic nervous system, including adrenal-derived pheochromocytomas
SUCNR1 expression is induced by hypoxia, extracellular succinate, and loss of SDHB in hPheo1, and SUCNR1 signaling increases viability in PC12 cells
Under hypoxia, an up to 30fold increase in succinate to fumarate ratio was reached in shSdhb64
Summary
Paragangliomas (PGLs) are catecholamine-producing chromaffin tumors of the autonomic nervous system, including adrenal-derived pheochromocytomas (together PPGLs). While curative in the majority of cases, resection is not an option for many paragangliomas with loss-of-function mutations of succinate dehydrogenase (SDH) subunits A-D (summarized as SDHx). Mutations in the SDHB gene predispose to metastases (34–69%) [1,2,3,4], usually making complete resection impossible. Mutations in SDHA, SDHC, and SDHD subunits predominantly cause head and neck PGLs (HNPs) [5,6,7], which can be inoperable due to proximity to vital structures such as vessels or nerves. Surgical complication rate is high, for carotid body location, causing nerve damage in 48% of cases, including 17% with permanent damage [8]. Treatment options for inoperable cases are extremely limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is urgently needed
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