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

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2019 May 1

PMID 31035382

Citations 23

Authors

Nicole Bechmann

Isabel Poser

Verena Seifert

Christian Greunke

Martin Ullrich

Nan Qin

Axel Walch

Mirko Peitzsch

Mercedes Robledo

Karel Pacak

Jens Pietzsch

Susan Richter

Graeme Eisenhofer

Affiliations

Soon will be listed here.

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 (MPC and MTT) or expressing both and (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 and -driven effects we expressed in MTT and MPC-mCherry cells (naturally lacking ). Presence of 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 in PC12 diminished these effects. Pseudohypoxic conditions, simulated by expression of 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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