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

Ángelo Torres, Jose Ignacio Erices, Fabiola Sanchez, Pamela Ehrenfeld, Laurent Turchi, Thierry Virolle, Daniel Uribe, Ignacio Niechi, Carlos Spichiger, José Dellis Rocha, Marcos Ramirez, Flavio Salazar-Onfray, Rody San Martín, Claudia Quezada

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)112-122
Number of pages11
JournalCancer Letters
Volume446
DOIs
Publication statusPublished - 1 Apr 2019
Externally publishedYes

Keywords

  • A Adenosine Receptor
  • Ectonucleotidase
  • Epithelial-Mesenchymal Transition
  • Hypoxia-Inducible Factors
  • Prostatic Acid Phosphatase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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