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

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

  • Front Endocrinol (Lausanne). 2021 Mar 12:12:589451. doi: 10.3389/fendo.2021.589451.
Dieter M Matlac 1,  Katerina Hadrava Vanova 2 3,  Nicole Bechmann 4,  Susan Richter 4,  Julica Folberth 5,  Hans K Ghayee 6,  Guang-Bo Ge 7,  Luma Abunimer 3,  Robert Wesley 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15,  Redouane Aherrahrou 8 9,  Margo Dona 10,  Ángel M Martínez-Montes 11,  Bruna Calsina 11,  Maria J Merino 12,  Markus Schwaninger 5,  Peter M T Deen 13,  Zhengping Zhuang 14,  Jiri Neuzil 2 15,  Karel Pacak 3,  Hendrik Lehnert 1,  Stephanie M J Fliedner 1
Affiliations

Affiliations

  • 1 Neuroendocrine Oncology and Metabolism, Medical Department I, Center of Brain, Behavior, and Metabolism, University Medical Center Schleswig-Holstein Lübeck, Lübeck, Germany.
  • 2 Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czechia.
  • 3 Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
  • 4 Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • 5 Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
  • 6 Department of Medicine, Division of Endocrinology, University of Florida and Malcom Randall VA Medical Center, Gainesville, FL, United States.
  • 7 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 8 Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
  • 9 Department of Biomedical Engineering, Centre for Public Health Genomics, University of Virginia, Charlottesville, VA, United States.
  • 10 Division of Endocrinology 471, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
  • 11 Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 12 Laboratory of Surgical Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
  • 13 Radboud University, Nijmegen, Netherlands.
  • 14 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
  • 15 School of Medical Science, Griffith University, Southport, QLD, Australia.
PMID: 33776908 DOI: 10.3389/fendo.2021.589451
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.

Keywords

SDHB gene; SUCNR1 (GPR91); paraganglioma; succinate; succinate receptor 1.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z