Upregulation of Epithelial-To-Mesenchymal Transition Markers and P2X7 Receptors Is Associated to Increased Invasiveness Caused by P2X7 Receptor Stimulation in Human Glioblastoma Stem Cells

Ziberi, Sihana; Zuccarini, Mariachiara; Carluccio, Marzia; Giuliani, Patricia; Ricci-Vitiani, Lucia; Pallini, Roberto; Caciagli, Francesco; Di Iorio, Patrizia; Ciccarelli, Renata

doi:10.3390/cells9010085

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Upregulation of Epithelial-To-Mesenchymal Transition Markers and P2X7 Receptors Is Associated to Increased Invasiveness Caused by P2X7 Receptor Stimulation in Human Glioblastoma Stem Cells

Sihana Ziberi

^1,2,3,†,

Mariachiara Zuccarini

^1,2,†,

^1,2,3,

^1,2,

⁴,

⁵,

²,

^1,2 and

^1,2,3,*

Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100 Chieti, Italy

Center for Advanced Study and Technologies (CAST). University of Chieti-Pescara, Via L. Polacchi, 66100 Chieti, Italy

StemTeCh Group, Via L. Polacchi, 66100 Chieti, Italy

⁴

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Via Regina Elena 299, 00161 Rome, Italy

⁵

Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168 Rome, Italy

Author to whom correspondence should be addressed.

^†

equally contributed.

Cells 2020, 9(1), 85; https://doi.org/10.3390/cells9010085

Received: 25 November 2019 / Revised: 23 December 2019 / Accepted: 25 December 2019 / Published: 29 December 2019

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)

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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. View Full-Text

Keywords: glioblastoma stem cells (GSCs); epithelial-to-mesenchymal transition (EMT) markers; GSC invasiveness; transforming growth factor beta; BzATP; P2X7 receptor splice variants A and B

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MDPI and ACS Style

Ziberi, S.; Zuccarini, M.; Carluccio, M.; Giuliani, P.; Ricci-Vitiani, L.; Pallini, R.; Caciagli, F.; Di Iorio, P.; Ciccarelli, R. Upregulation of Epithelial-To-Mesenchymal Transition Markers and P2X7 Receptors Is Associated to Increased Invasiveness Caused by P2X7 Receptor Stimulation in Human Glioblastoma Stem Cells. Cells 2020, 9, 85. https://doi.org/10.3390/cells9010085

AMA Style

Ziberi S, Zuccarini M, Carluccio M, Giuliani P, Ricci-Vitiani L, Pallini R, Caciagli F, Di Iorio P, Ciccarelli R. Upregulation of Epithelial-To-Mesenchymal Transition Markers and P2X7 Receptors Is Associated to Increased Invasiveness Caused by P2X7 Receptor Stimulation in Human Glioblastoma Stem Cells. Cells. 2020; 9(1):85. https://doi.org/10.3390/cells9010085

Chicago/Turabian Style

Ziberi, Sihana, Mariachiara Zuccarini, Marzia Carluccio, Patricia Giuliani, Lucia Ricci-Vitiani, Roberto Pallini, Francesco Caciagli, Patrizia Di Iorio, and Renata Ciccarelli. 2020. "Upregulation of Epithelial-To-Mesenchymal Transition Markers and P2X7 Receptors Is Associated to Increased Invasiveness Caused by P2X7 Receptor Stimulation in Human Glioblastoma Stem Cells" Cells 9, no. 1: 85. https://doi.org/10.3390/cells9010085

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Upregulation of Epithelial-To-Mesenchymal Transition Markers and P2X7 Receptors Is Associated to Increased Invasiveness Caused by P2X7 Receptor Stimulation in Human Glioblastoma Stem Cells

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