Regulation of epinephrine biosynthesis in HRAS-mutant paragangliomas

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

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.

Details

Original languageEnglish
Article numbere230230
JournalEndocrine-related cancer
Volume30
Issue number12
Publication statusPublished - 1 Dec 2023
Peer-reviewedYes

External IDs

Scopus 85175404976
ORCID /0000-0002-6932-333X/work/148144948
ORCID /0000-0002-3549-2477/work/148145341

Keywords

Keywords

  • Humans, Pheochromocytoma/genetics, Proto-Oncogene Proteins p21(ras), Adrenal Gland Neoplasms/genetics, Paraganglioma/genetics, Epinephrine