Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial–Mesenchymal Transition-Like Reprogramming
| Autor: | Daniel Hänggi, Christoph Janiak, Donata Maciaczyk, Silke Neumann, Katharina Koch, Beatriz Giesen, Julia Tsiampali, Jaroslaw Maciaczyk |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
endocrine system Pharmaceutical Science lcsh:Medicine lcsh:RS1-441 epithelial–mesenchymal transition Article Pentoxifylline lcsh:Pharmacy and materia medica 03 medical and health sciences 0302 clinical medicine Glioma Drug Discovery drug targets medicine Epithelial–mesenchymal transition Phosphodiesterase inhibitor Activator (genetics) Chemistry fungi lcsh:R glioblastoma medicine.disease Adenosine In vitro nervous system diseases 030104 developmental biology adenosine 030220 oncology & carcinogenesis Cancer research CD73 Molecular Medicine A3AR Reprogramming medicine.drug |
| Zdroj: | Pharmaceuticals, Vol 13, Iss 378, p 378 (2020) Pharmaceuticals Volume 13 Issue 11 |
| ISSN: | 1424-8247 |
| Popis: | 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&ndash 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. |
| Databáze: | OpenAIRE |
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