Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia. (1st April 2019)

• Record Type: Journal Article
• Authors: Torres, Ángelo; Erices, Jose Ignacio; Sanchez, Fabiola; Ehrenfeld, Pamela; Turchi, Laurent; Virolle, Thierry; Uribe, Daniel; Niechi, Ignacio; Spichiger, Carlos; Rocha, José Dellis; Ramirez, Marcos; Salazar-Onfray, Flavio; San Martín, Rody; Quezada, Claudia
• Is Part Of: Cancer letters. Volume 446(2019)
• Page Start: 112
• Page End: 122
• Publication Date: 2019-04-01
• Subjects: A3 Adenosine Receptor -- Ectonucleotidase -- Epithelial-Mesenchymal Transition -- Prostatic Acid Phosphatase -- Hypoxia-Inducible Factors; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.01.004
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Glioblastoma (GBM) is the brain tumor with the worst prognosis composed of a cell subpopulation called Glioblastoma Stem-like Cells (GSCs) responsible for tumor recurrence mediated by cell invasion. GSCs persist in a hypoxic microenvironment which promotes extracellular adenosine production and activation of the A3 Adenosine Receptor (A3 AR), therefore, the aim of this study was to determine the role of extracellular adenosine and A3 AR on GSCs invasion under hypoxia. GSCs were obtained from a U87MG cell line and primary cultures of GBM patients, and then incubated under normoxia or hypoxia. Gene expression was evaluated by RNAseq, RT-qPCR, and western blot. Cell migration was measured by spreading and transwell boyden chamber assays; cell invasion was evaluated by Matrigel-coated transwell, ex vivo brain slice, and in vivo xenograft assays. The contribution of A3 AR on cell migration/invasion was evaluated using the A3 AR antagonist, MRS1220. Extracellular adenosine production was higher under hypoxia than normoxia, mainly by the catalytic action of the prostatic acid phosphatase (PAP), promoting cell migration/invasion in a HIF-2-dependent process. A3 AR blockade decreased cell migration/invasion and the expression of Epithelial-Mesenchymal Transition markers. In conclusion, high levels of extracellular adenosine production enhance cell migration/invasion of GSCs, through HIF-2/PAP-dependent activation of A3 AR under hypoxia. Highlights: HIFs increase extracellular adenosine production under hypoxia in GSCs. Ectonucleotidases expression is HIFs-dependent under hypoxia in GSCs. Invasion and migration of GSCs decrease when HIF-2 and PAP are silenced. Epithelial-mesenchymal transition is regulated by A3 AR in GSCs under hypoxia.