Regulation of epinephrine biosynthesis in HRAS-mutant paragangliomas

Author:

Li Minghao12,Richter Susan3,Mohr Hermine4,Drukewitz Stephan56,Poser Isabel3,Stanke Daniela3,Calsina Bruna7ORCID,Martinez-Montes Angel M7,Quinkler Marcus8,Timmers Henri J L M9,Nölting Svenja1011,Beuschlein Felix1011,Remde Hanna12,Opocher Giuseppe13,Rapizzi Elena14ORCID,Pacak Karel15ORCID,Pamporaki Christina1,Robledo Mercedes7ORCID,Liu Longfei2ORCID,Jiang Jingjing16,Bornstein Stefan R1,Eisenhofer Graeme1,Fliedner Stephanie M J17,Bechmann Nicole3ORCID

Affiliation:

1. Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany

2. Department of Urology, Xiangya Hospital, Central South University, Changsha, China

3. Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

4. Institute for Diabetes and Cancer, Helmholtz Centre Munich, Neuherberg, Germany

5. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany

6. Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany

7. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

8. Endocrinology in Charlottenburg, Berlin, Germany

9. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

10. Medizinische Klinik Und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany

11. Department of Endocrinology, Diabetology and Clinical Nutrition, Universitätsspital Zürich (USZ) and University of Zurich (UZH), Zurich, Switzerland

12. Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany

13. Department of Medicine, University of Padua, Padua, Italy

14. Department of Experimental and Clinical Medicine, University of Florence, Italy

15. Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States

16. Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China

17. University Cancer Center Schleswig-Holstein, University Medical Center Schleswig-Holsten, Lübeck, Germany

Abstract

The biochemical phenotype of paragangliomas (PGLs) is highly dependent on the underlying genetic background and tumor location. PGLs at extra-adrenal locations usually do not express phenylethanolamine N-methyltransferase (PNMT), the enzyme required for epinephrine production, which was explained by the absence of glucocorticoids. PGLs with pathogenic variants (PVs) in Harvey rat sarcoma viral oncogene homolog (HRAS) can occur in or outside of the adrenal, but always synthesize epinephrine independently of the localization. Here, we characterize the signaling pathways through which PVs in HRAS influence PNMT expression. Catecholamines, cortisol, and transcriptional features of PGL tissues with known genetic background were analyzed. Genetically modified rat pheochromocytoma cells carrying PVs in Hras were generated and analyzed for regulation of Pnmt expression. Elevated epinephrine contents in PGLs with PVs in HRAS were accompanied by enrichment in mitogen-activated protein kinase (MAPK) signaling compared to PGLs with PVs in genes that activate hypoxia pathways. In vitro, Hras PVs increased Pnmt expression and epinephrine biosynthesis through increased phosphorylation of stimulatory protein 1 via MAPK signaling. Here, we provide a molecular mechanism that explains the PV-dependent epinephrine production of PGLs.

Publisher

Bioscientifica

Subject

Cancer Research,Endocrinology,Oncology,Endocrinology, Diabetes and Metabolism

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