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.

Genetic Impairment of Succinate Metabolism Disrupts Bioenergetic Sensing in Adrenal Neuroendocrine Cancer

“…Succinate buildup stemming from loss of function of SDHx enzyme complex contributes to a plethora of pathophysiological processes. Previously, several downstream effects of succinate accumulation have been linked to altered metabolism, pseudohypoxic HIF1/2 stabilization, oxidative stress, SUCNR1 activation and tumor-associated inflammation (Dahia et al, 2005;Matlac et al, 2021;Pollard et al, 2006). Though these mechanisms have been demonstrated to serve as components in discrete cellular-or disease-specific contexts, their suggested interactions as part of the multistep process of carcinogenesis have not been fully delineated.…”

“…]i homeostasis through autocrine signaling. Specifically, excessive succinate freely shuttles between the mitochondria, cytosol, and across the cell membrane to stimulate the SUCNR1 receptor in SDHx related PC tumors (Matlac et al, 2021).…”

Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors

“…Recently, Wallace et al showed that assessment of Krebs cycle related metabolites by using LC-MS/MS in addition to immunohistochemistry improved the diagnosis of SDH impairment at a functional level (42). These tumoral metabolic pathway alterations translate into characteristic secretory pattern of catecholamine metabolites which contribute to the diagnosis of malignancy (39,(43)(44)(45)(46). Of note, they also appear to have therapeutic relevance (39,(43)(44)(45).…”

“…These tumoral metabolic pathway alterations translate into characteristic secretory pattern of catecholamine metabolites which contribute to the diagnosis of malignancy (39,(43)(44)(45)(46). Of note, they also appear to have therapeutic relevance (39,(43)(44)(45).…”

Oncometabolites drive tumorigenesis by enhancing protein acylation: from chromosomal remodelling to nonhistone modification

“…In addition to being involved in metabolic pathways and energy supply, metabolites trigger oncogenic signalling via noncovalent interactions with macromolecules, mainly involved in competitive inhibition or allostery [ 1 ]. In one noteworthy example, the signalling molecule succinate binds to and activates succinate receptor 1 (SUCNR1) to promote tumour cell proliferation and metastasis [ 6 – 8 ]. Importantly, metabolites have been shown to possess nonmetabolic functions because of direct protein modifications, which are distinguished from other modifications, such as ubiquitination and sumoylation.…”