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Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells

Pheochromocytomas and paragangliomas (PPGLs) with activated pseudohypoxic pathways are associated with an immature catecholamine phenotype and carry a higher risk for metastasis. For improved understanding of the underlying mechanisms we investigated the impact of hypoxia and pseudohypoxia on catech...

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Autores principales: Bechmann, Nicole, Poser, Isabel, Seifert, Verena, Greunke, Christian, Ullrich, Martin, Qin, Nan, Walch, Axel, Peitzsch, Mirko, Robledo, Mercedes, Pacak, Karel, Pietzsch, Jens, Richter, Susan, Eisenhofer, Graeme
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562431/
https://www.ncbi.nlm.nih.gov/pubmed/31035382
http://dx.doi.org/10.3390/cancers11050594
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author Bechmann, Nicole
Poser, Isabel
Seifert, Verena
Greunke, Christian
Ullrich, Martin
Qin, Nan
Walch, Axel
Peitzsch, Mirko
Robledo, Mercedes
Pacak, Karel
Pietzsch, Jens
Richter, Susan
Eisenhofer, Graeme
author_facet Bechmann, Nicole
Poser, Isabel
Seifert, Verena
Greunke, Christian
Ullrich, Martin
Qin, Nan
Walch, Axel
Peitzsch, Mirko
Robledo, Mercedes
Pacak, Karel
Pietzsch, Jens
Richter, Susan
Eisenhofer, Graeme
author_sort Bechmann, Nicole
collection PubMed
description Pheochromocytomas and paragangliomas (PPGLs) with activated pseudohypoxic pathways are associated with an immature catecholamine phenotype and carry a higher risk for metastasis. For improved understanding of the underlying mechanisms we investigated the impact of hypoxia and pseudohypoxia on catecholamine biosynthesis in pheochromocytoma cells naturally lacking Hif2α (MPC and MTT) or expressing both Hif1α and Hif2α (PC12). Cultivation under extrinsic hypoxia or in spheroid culture (intrinsic hypoxia) increased cellular dopamine and norepinephrine contents in all cell lines. To distinguish further between Hif1α- and Hif2α-driven effects we expressed Hif2α in MTT and MPC-mCherry cells (naturally lacking Hif2α). Presence of Hif2α resulted in similarly increased cellular dopamine and norepinephrine under hypoxia as in the control cells. Furthermore, hypoxia resulted in enhanced phosphorylation of tyrosine hydroxylase (TH). A specific knockdown of Hif1α in PC12 diminished these effects. Pseudohypoxic conditions, simulated by expression of Hif2α under normoxia resulted in increased TH phosphorylation, further stimulated by extrinsic hypoxia. Correlations with PPGL tissue data led us to conclude that catecholamine biosynthesis under hypoxia is mainly mediated through increased phosphorylation of TH, regulated as a short-term response (24–48 h) by HIF1α. Continuous activation of hypoxia-related genes under pseudohypoxia leads to a HIF2α-mediated phosphorylation of TH (permanent status).
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spelling pubmed-65624312019-06-17 Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells Bechmann, Nicole Poser, Isabel Seifert, Verena Greunke, Christian Ullrich, Martin Qin, Nan Walch, Axel Peitzsch, Mirko Robledo, Mercedes Pacak, Karel Pietzsch, Jens Richter, Susan Eisenhofer, Graeme Cancers (Basel) Article Pheochromocytomas and paragangliomas (PPGLs) with activated pseudohypoxic pathways are associated with an immature catecholamine phenotype and carry a higher risk for metastasis. For improved understanding of the underlying mechanisms we investigated the impact of hypoxia and pseudohypoxia on catecholamine biosynthesis in pheochromocytoma cells naturally lacking Hif2α (MPC and MTT) or expressing both Hif1α and Hif2α (PC12). Cultivation under extrinsic hypoxia or in spheroid culture (intrinsic hypoxia) increased cellular dopamine and norepinephrine contents in all cell lines. To distinguish further between Hif1α- and Hif2α-driven effects we expressed Hif2α in MTT and MPC-mCherry cells (naturally lacking Hif2α). Presence of Hif2α resulted in similarly increased cellular dopamine and norepinephrine under hypoxia as in the control cells. Furthermore, hypoxia resulted in enhanced phosphorylation of tyrosine hydroxylase (TH). A specific knockdown of Hif1α in PC12 diminished these effects. Pseudohypoxic conditions, simulated by expression of Hif2α under normoxia resulted in increased TH phosphorylation, further stimulated by extrinsic hypoxia. Correlations with PPGL tissue data led us to conclude that catecholamine biosynthesis under hypoxia is mainly mediated through increased phosphorylation of TH, regulated as a short-term response (24–48 h) by HIF1α. Continuous activation of hypoxia-related genes under pseudohypoxia leads to a HIF2α-mediated phosphorylation of TH (permanent status). MDPI 2019-04-28 /pmc/articles/PMC6562431/ /pubmed/31035382 http://dx.doi.org/10.3390/cancers11050594 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bechmann, Nicole
Poser, Isabel
Seifert, Verena
Greunke, Christian
Ullrich, Martin
Qin, Nan
Walch, Axel
Peitzsch, Mirko
Robledo, Mercedes
Pacak, Karel
Pietzsch, Jens
Richter, Susan
Eisenhofer, Graeme
Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells
title Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells
title_full Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells
title_fullStr Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells
title_full_unstemmed Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells
title_short Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells
title_sort impact of extrinsic and intrinsic hypoxia on catecholamine biosynthesis in absence or presence of hif2α in pheochromocytoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562431/
https://www.ncbi.nlm.nih.gov/pubmed/31035382
http://dx.doi.org/10.3390/cancers11050594
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