Minghao Li, Susan Richter, Hermine Mohr, Stephan Drukewitz, Isabel Poser, Daniela Stanke, Bruna Calsina, Angel M Martinez-Montes, Marcus Quinkler, Henri J L M Timmers, Svenja Nölting, Felix Beuschlein, Hanna Remde, Giuseppe Opocher, Elena Rapizzi, Karel Pacak, Christina Pamporaki, Mercedes Robledo, Longfei Liu, Jingjing Jiang, Stefan R Bornstein, Graeme Eisenhofer, Stephanie M J Fliedner, Nicole Bechmann
{"title":"Regulation of epinephrine biosynthesis in HRAS-mutant paragangliomas.","authors":"Minghao Li, Susan Richter, Hermine Mohr, Stephan Drukewitz, Isabel Poser, Daniela Stanke, Bruna Calsina, Angel M Martinez-Montes, Marcus Quinkler, Henri J L M Timmers, Svenja Nölting, Felix Beuschlein, Hanna Remde, Giuseppe Opocher, Elena Rapizzi, Karel Pacak, Christina Pamporaki, Mercedes Robledo, Longfei Liu, Jingjing Jiang, Stefan R Bornstein, Graeme Eisenhofer, Stephanie M J Fliedner, Nicole Bechmann","doi":"10.1530/ERC-23-0230","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":93989,"journal":{"name":"Endocrine-related cancer","volume":"30 12","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Endocrine-related cancer","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1530/ERC-23-0230","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/12/1 0:00:00","PubModel":"Print","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
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.