Abstract
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.
Highlights
Glioblastoma (GBM) is the most common and most aggressive primary brain tumour with a very poor median overall survival of less than two years [1]
Since Zinc Finger E-Box Binding Homeobox 1 (ZEB1) is a pivotal player in Epithelial-to-mesenchymal-like transition (EMT) in these regions [27], we evaluated the effect of ZEB1 knockdown on CD73 expression
Hanodwpervoelirf,etrhateioenffe[1c5t,3o4f].AM3AorRe bsploeckifiacdalelyo, nwCe Dsh7o3waenddtShNatAthILe 1efwfeacstsvoanriaGbSlCe and no commopnrofeliafetruarteiosncaonudldclobneogfoenuincidtyiwnetrheeintdeesptenddceuntltfurormesi(tsFeignuzyrme a6tdic).acFtiuvrittyhbeurmt doerpee,nEdeMntTomn tohde ulation led to aCdDec7r3eparsoeteiinn Alev3Ael.RHporwoetveeinr, einxpcornetsrsaisotnto(Fpirgevuiroeus6efi)n.dings [34,35], selective inhibition of CD73 enzymatic activity by APCP had significant effects only on the invasiveness of glioma stem-like cells (GSCs)
Summary
Glioblastoma (GBM) is the most common and most aggressive primary brain tumour with a very poor median overall survival of less than two years [1]. Current treatments for GBM include surgical resection of the tumour, followed by radiotherapy and chemotherapy with temozolomide (TMZ) [2]. A subpopulation of cells, glioma stem-like cells (GSCs), characterised by expression of neural stem cell markers and self-renewing capability, contribute to tumour insurgence, progression, recurrence and chemo-resistance [3,4]. Given that GSCs are resistant to the current standard treatment, refined therapeutic approaches targeting this particular subpopulation are needed. Epithelial-to-mesenchymal-like transition (EMT) has been identified as one of the mechanisms that governs GBM cell dissemination, disease progression and relapse after treatment [5]. During the acquisition of mesenchymal properties, the cells lose their tight connections and become more invasive gaining stem-cell characteristics [6]. EMT-like changes seem to be crucial for tumour initiation, progression, invasion and therapy resistance in GBM [7]. The transcriptional factor Zinc Finger E-Box Binding Homeobox 1 (ZEB1) is one of the main activators of this molecular switch, together with ZEB2, SNAIL1/SNAIL2 and TWIST1 [8,9,10]
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