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Li, M.* ; Richter, S.* ; Mohr, H. ; Drukewitz, S.* ; Poser, I.* ; Stanke, D.* ; Calsina, B.* ; Martinez-Montes, A.M.* ; Quinkler, M.* ; Timmers, H.J.L.M.* ; Nölting, S.* ; Beuschlein, F.* ; Remde, H.* ; Opocher, G.* ; Rapizzi, E.* ; Pacak, K.* ; Pamporaki, C.* ; Robledo, M.* ; Liu, L.* ; Jiang, J.* ; Bornstein, S.* ; Eisenhofer, G.* ; Fliedner, S.M.J.* ; Bechmann, N.*

Regulation of epinephrine biosynthesis in HRAS-mutant paragangliomas.

Endocr. Relat. Cancer 30:12 (2023)

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Open Access Green as soon as Postprint is submitted to ZB.

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Mapk Pathway ; Catecholamines ; Glucocorticoids ; Paraganglioma ; Phenotype–genotype Correlations; Phenylethanolamine N-methyltransferase; H-ras; Pheochromocytoma; Hif2-alpha; Phenotypes; Mutations; Plasma; Gene

ISSN (print) / ISBN 1351-0088

e-ISSN 1479-6821

Journal Endocrine-Related Cancer

Quellenangaben Volume: 30, Issue: 12 Article Number: 12

Publisher BioScientifica

Publishing Place Bristol

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Cancer (IDC)

Grants
China Scholarship Council
National Natural Science Foundation of China
Paradifference Foundation
Accion Estrategica en Salud, cofinanciado a traves del Fondo Europeo de Desarrollo Regional (FEDER))
Umbrella of University Medicine Zurich
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)