Abstract
Glioblastoma (GBM) stem cells (GSCs), which contribute to GBM unfavorable prognosis, show high expression levels of ATP/P2X7 receptors (P2X7R). Here, we reported that cells exposure to 2’(3’)-O-(4-benzoylbenzoyl)-ATP (BzATP), a P2X7R agonist, up-regulated the expression of markers associated to epithelial-to-mesenchymal transition (EMT), a process likely contributing to GSC malignancy, and increased GSC migration/invasiveness like the known EMT inducer, Transforming Growth Factor β1 (TGFβ1). These effects were coupled to phosphorylation of SMAD2, a downstream effector in the TGFβ pathway, suggesting its involvement in P2X7R-mediated activity in GSCs. All BzATP effects, including a decrease in the caspase 3/7 activity in GSC medium, were mostly counteracted by the P2X7R antagonist A438079. Finally, BzATP increased the subunit expression of two main human P2X7R splice variants, the full-length P2X7A and the truncated P2X7B, lacking the carboxylic tail, which have different functional properties depending on their arrangement. Since up-regulation of A/B subunits might favor their assembly into a heterotrimeric P2X7R with great sensitivity towards agonists and cell energy support, this is in line with increased EMT markers expression, cell migration/invasion and GSC survival observed following P2X7R stimulation. As in GBM microenvironment extracellular ATP levels may activate P2X7R, our data suggest a P2X7R role in GBM recurrence/invasiveness.
Highlights
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, characterized by high invasiveness and recurrence [1]
glioblastoma stem cells (GSCs) can be isolated from tumor specimens and cultured in vitro in conditions favoring the growth of neural stem cells, which allow them to mimic the phenotype and genotype of primary tumors more closely than serum-cultured cell lines [3,4]
Our findings showed that P2X7 receptor (P2X7R) activation upregulated epithelial-to-mesenchymal transition (EMT) marker expression and increased cell invasiveness in the examined cells, protecting them from apoptotic events
Summary
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, characterized by high invasiveness and recurrence [1]. The P2X7BR variant, lacking the pore, is today regarded as a pro-cancerous receptor, able to increase tumor growth and invasiveness [26,27] Based on these premises, we aimed our study at investigating, in GSCs, the influence of P2X7R activation on: i) EMT process, ii) cell migration/invasion, iii) expression of P2X7R, with a particular interest towards the two main splice variants A and B. Our findings showed that P2X7R activation upregulated EMT marker expression and increased cell invasiveness in the examined cells, protecting them from apoptotic events These effects were coupled to increased expression of the two P2X7R splice variants, the co-assembly of which into a hetero-trimeric receptor would likely support the pro-tumor effect consequent to GSC exposure to relatively low concentrations of the P2X7R agonist, BzATP
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