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Article

Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial–Mesenchymal Transition-Like Reprogramming

1
Neurosurgery Department, University Hospital Duesseldorf, 40225 Duesseldorf, Germany
2
Department of Pathology, University of Otago, Dunedin 9016, New Zealand
3
Institute of Inorganic Chemistry and Structural Chemistry, Heinrich Heine University Duesseldorf, 40225 Duesseldorf, Germany
4
IUF-Leibniz Research Institute for Environmental Medicine, 40225 Duesseldorf, Germany
5
Department of Neurosurgery, University Hospital Bonn, 53179 Bonn, Germany
6
Department of Surgical Sciences, University of Otago, Dunedin 9016, New Zealand
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2020, 13(11), 378; https://doi.org/10.3390/ph13110378
Received: 23 September 2020 / Revised: 27 October 2020 / Accepted: 6 November 2020 / Published: 11 November 2020
(This article belongs to the Special Issue Immune Checkpoint Inhibitor Therapy)
Glioblastoma (GBM) is the most aggressive malignant primary brain tumour in adulthood. Despite strong research efforts current treatment options have a limited impact on glioma stem-like cells (GSCs) which contribute to GBM formation, progression and chemoresistance. Invasive growth of GSCs is in part associated with epithelial–mesenchymal-like transition (EMT), a mechanism associated with CD73 in several cancers. Here, we show that CD73 regulates the EMT activator SNAIL1 and further investigate the role of enzymatic and non-enzymatic CD73 activity in GBM progression. Reduction of CD73 protein resulted in significant suppression of GSC viability, proliferation and clonogenicity, whereas CD73 enzymatic activity exhibited negative effects only on GSC invasion involving impaired downstream adenosine (ADO) signalling. Furthermore, application of phosphodiesterase inhibitor pentoxifylline, a potent immunomodulator, effectively inhibited ZEB1 and CD73 expression and significantly decreased viability, clonogenicity, and invasion of GSC in vitro cultures. Given the involvement of adenosine and A3 adenosine receptor in GSC invasion, we investigated the effect of the pharmacological inhibition of A3AR on GSC maintenance. Direct A3AR inhibition promoted apoptotic cell death and impaired the clonogenicity of GSC cultures. Taken together, our data indicate that CD73 is an exciting novel target in GBM therapy. Moreover, pharmacological interference, resulting in disturbed ADO signalling, provides new opportunities to innovate GBM therapy. View Full-Text
Keywords: A3AR; adenosine; CD73; drug targets; epithelial–mesenchymal transition; glioblastoma A3AR; adenosine; CD73; drug targets; epithelial–mesenchymal transition; glioblastoma
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MDPI and ACS Style

Tsiampali, J.; Neumann, S.; Giesen, B.; Koch, K.; Maciaczyk, D.; Janiak, C.; Hänggi, D.; Maciaczyk, J. Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial–Mesenchymal Transition-Like Reprogramming. Pharmaceuticals 2020, 13, 378. https://doi.org/10.3390/ph13110378

AMA Style

Tsiampali J, Neumann S, Giesen B, Koch K, Maciaczyk D, Janiak C, Hänggi D, Maciaczyk J. Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial–Mesenchymal Transition-Like Reprogramming. Pharmaceuticals. 2020; 13(11):378. https://doi.org/10.3390/ph13110378

Chicago/Turabian Style

Tsiampali, Julia, Silke Neumann, Beatriz Giesen, Katharina Koch, Donata Maciaczyk, Christoph Janiak, Daniel Hänggi, and Jaroslaw Maciaczyk. 2020. "Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial–Mesenchymal Transition-Like Reprogramming" Pharmaceuticals 13, no. 11: 378. https://doi.org/10.3390/ph13110378

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