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

Resultado de la investigación: Article

3 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)112-122
Número de páginas11
PublicaciónCancer Letters
Volumen446
DOI
EstadoPublished - 1 abr 2019
Publicado de forma externa

Huella dactilar

Adenosine A3 Receptors
Glioblastoma
Adenosine
Cell Movement
Stem Cells
Adenosine A3 Receptor Antagonists
Epithelial-Mesenchymal Transition
Hypoxia
Heterografts
Brain Neoplasms
Western Blotting
Gene Expression
Recurrence
Cell Line
Brain

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Citar esto

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. / Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia. En: Cancer Letters. 2019 ; Vol. 446. pp. 112-122.
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title = "Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia",
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.",
keywords = "A Adenosine Receptor, Ectonucleotidase, Epithelial-Mesenchymal Transition, Hypoxia-Inducible Factors, Prostatic Acid Phosphatase",
author = "{\'A}ngelo Torres and Erices, {Jose Ignacio} and Fabiola Sanchez and Pamela Ehrenfeld and Laurent Turchi and Thierry Virolle and Daniel Uribe and Ignacio Niechi and Carlos Spichiger and Rocha, {Jos{\'e} Dellis} and Marcos Ramirez and Flavio Salazar-Onfray and {San Mart{\'i}n}, Rody and Claudia Quezada",
year = "2019",
month = "4",
day = "1",
doi = "10.1016/j.canlet.2019.01.004",
language = "English",
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Torres, Á, 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 2019, 'Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia', Cancer Letters, vol. 446, pp. 112-122. https://doi.org/10.1016/j.canlet.2019.01.004

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

En: Cancer Letters, Vol. 446, 01.04.2019, p. 112-122.

Resultado de la investigación: Article

TY - JOUR

T1 - Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia

AU - Torres, Ángelo

AU - Erices, Jose Ignacio

AU - Sanchez, Fabiola

AU - Ehrenfeld, Pamela

AU - Turchi, Laurent

AU - Virolle, Thierry

AU - Uribe, Daniel

AU - Niechi, Ignacio

AU - Spichiger, Carlos

AU - Rocha, José Dellis

AU - Ramirez, Marcos

AU - Salazar-Onfray, Flavio

AU - San Martín, Rody

AU - Quezada, Claudia

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

KW - A Adenosine Receptor

KW - Ectonucleotidase

KW - Epithelial-Mesenchymal Transition

KW - Hypoxia-Inducible Factors

KW - Prostatic Acid Phosphatase

UR - http://www.scopus.com/inward/record.url?scp=85060472467&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2019.01.004

DO - 10.1016/j.canlet.2019.01.004

M3 - Article

C2 - 30660649

AN - SCOPUS:85060472467

VL - 446

SP - 112

EP - 122

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

ER -