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Helm, J.* ; Drukewitz, S.* ; Poser, I.* ; Richter, S.* ; Friedemann, M.* ; William, D.* ; Mohr, H. ; Nölting, S.* ; Robledo, M.* ; Bornstein, S.R.* ; Eisenhofer, G.* ; Bechmann, N.*

Treatment of pheochromocytoma cells with recurrent cycles of hypoxia: A new pseudohypoxic in vitro model.

Cells 11:560 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Continuous activation of hypoxia pathways in pheochromocytomas and paragangliomas (PPGLs) is associated with higher disease aggressiveness, for which effective treatment strategies are still missing. Most of the commonly used in vitro models lack characteristics of these pseudohypoxic tumors, including elevated expression of hypoxia-inducible factor (HIF) 2α. To address this shortcoming, we investigated whether recurrent hypoxia cycles lead to continuous activation of hypoxia pathways under normoxic conditions and whether this pseudohypoxia is associated with increased cellular aggressiveness. Rat pheochromocytoma cells (PC12) were incubated under hypoxia for 24 h every 3–4 days, up to 20 hypoxia–reoxygenation cycles, resulting in PC12 Z20 cells. PC12 Z20 control cells were obtained by synchronous cultivation under normoxia. RNA sequencing revealed upregulation of HIF2α in PC12 Z20 cells and a pseudohypoxic gene signature that overlapped with the gene signature of pseudohypoxic PPGLs. PC12 Z20 cells showed a higher growth rate, and the migration and adhesion capacity were significantly increased compared with control cells. Changes in global methylation, together with the pseudohypoxic conditions, may be responsible for the increased aggressiveness of this new model. The established sub-cell line with characteristics of pseudohypoxic PPGLs represent a complementary model for further investigations, for example, with regard to new therapeutic approaches.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Drug Resistance ; Epigenetic ; Hypermethylation ; Hypoxia Resistance ; Metastasis ; Paraganglioma ; Pheochromocytoma ; Pseudohypoxia; Tumor Hypoxia; Expression; Hif2-alpha; Hereditary; Genes
ISSN (print) / ISBN 2073-4409
e-ISSN 2073-4409
Journal Cells
Quellenangaben Volume: 11, Issue: 3, Pages: , Article Number: 560 Supplement: ,
Publisher MDPI
Publishing Place Basel
Non-patent literature Publications
Institute(s) Institute of Diabetes and Cancer (IDC)
Grants European Social Fund
Paradifference Foundation
Deutsche Forschungsgemeinschaft