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

1
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
2
Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328 Dresden, Germany
3
Research Unit Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
4
Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
5
German Consortium for Translational Cancer Research (DKTK), partner site Essen/Düsseldorf, 45147 Düsseldorf, Germany
6
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, 40225 Düsseldorf, Germany
7
Department of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
8
Hereditary Endocrine Cancer Group, CNIO, Madrid, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
9
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
10
Department of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstrasse 9, 01062 Dresden, Germany
11
Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 594; https://doi.org/10.3390/cancers11050594
Received: 26 March 2019 / Revised: 24 April 2019 / Accepted: 25 April 2019 / Published: 28 April 2019
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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Abstract

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). View Full-Text
Keywords: hypoxia; pseudohypoxia; spheroids; HIF; EPAS1; catecholamine; pheochromocytoma and paraganglioma; phosphorylation tyrosine hydroxylase hypoxia; pseudohypoxia; spheroids; HIF; EPAS1; catecholamine; pheochromocytoma and paraganglioma; phosphorylation tyrosine hydroxylase
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Bechmann, N.; Poser, I.; Seifert, V.; Greunke, C.; Ullrich, M.; Qin, N.; Walch, A.; Peitzsch, M.; Robledo, M.; Pacak, K.; Pietzsch, J.; Richter, S.; Eisenhofer, G. Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells. Cancers 2019, 11, 594.

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