Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia

Torres A, Erices JI, Sanchez F, Ehrenfeld P, Turchi L, Virolle T, Uribe D, Niechi I, Spichiger C, Rocha JD, Ramirez M, Salazar-Onfray F, San Martín R, Quezada C

Keywords: epithelial-mesenchymal transition, A(3) adenosine receptor, Ectonucleotidase, Hypoxia-Inducible Factors, Prostatic Acid Phosphatase.

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 (A3AR), therefore, the aim of this study was to determine the role of extracellular adenosine and A3AR 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 A3AR on cell migration/invasion was evaluated using the A3AR 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. A3AR 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 A3AR under hypoxia.

Más información

Título de la Revista: CANCER LETTERS
Volumen: 446
Editorial: ELSEVIER IRELAND LTD
Fecha de publicación: 2019
Página de inicio: 112
Página final: 122
Idioma: Ingles
URL: DOI: 10.1016/j.canlet.2019.01.004
Notas: ISI