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Regulation of epinephrine biosynthesis in HRAS-mutant paragangliomas

Minghao Li1,2, Susan Richter3, Hermine Mohr4

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

Endocrine-Related Cancer
|October 30, 2023
PubMed

Insights

Paragangliomas (PGLs) with Harvey rat sarcoma viral oncogene homolog (HRAS) mutations produce epinephrine independently of location. This occurs via mitogen-activated protein kinase (MAPK) signaling, which upregulates phenylethanolamine N-methyltransferase (PNMT) expression.

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • Paragangliomas (PGLs) exhibit diverse biochemical phenotypes influenced by genetics and location.
  • Extra-adrenal PGLs typically lack phenylethanolamine N-methyltransferase (PNMT), inhibiting epinephrine production due to low glucocorticoids.
  • Harvey rat sarcoma viral oncogene homolog (HRAS) pathogenic variants (PVs) in PGLs lead to epinephrine synthesis irrespective of tumor site.

Purpose of the Study:

  • To elucidate the signaling pathways by which HRAS PVs drive PNMT expression and epinephrine production in PGLs.
  • To understand the molecular mechanism underlying HRAS-driven epinephrine synthesis in paragangliomas.

Main Methods:

  • Analysis of catecholamines, cortisol, and transcriptional profiles in PGL tissues with known genetic backgrounds.
  • Generation and analysis of genetically modified rat pheochromocytoma cells with HRAS PVs to study Pnmt regulation.
  • In vitro experiments assessing the role of mitogen-activated protein kinase (MAPK) signaling in Hras-mutated cells.

Main Results:

  • PGLs with HRAS PVs showed elevated epinephrine levels and enriched mitogen-activated protein kinase (MAPK) signaling compared to PGLs with hypoxia-pathway gene PVs.
  • In vitro, HRAS PVs significantly increased Pnmt expression and epinephrine biosynthesis.
  • This increase was mediated by enhanced phosphorylation of stimulatory protein 1 through MAPK signaling.

Conclusions:

  • HRAS PVs induce epinephrine production in paragangliomas through a MAPK-dependent pathway.
  • This study provides a molecular explanation for the observed epinephrine synthesis in HRAS-mutated PGLs.
  • The findings highlight the critical role of HRAS and MAPK signaling in paraganglioma pathogenesis and catecholamine production.
Keywords:
MAPK pathwaycatecholaminesglucocorticoidsparagangliomaphenotype–genotype correlations

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