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The chemoresistance of GSCs is mediated in part by adenosine signaling and ABC transporters, which extrude drugs outside the cell, such as the multidrug resistance-associated proteins (MRPs) subfamily. Adenosine promotes MRP1-dependent chemoresistance under normoxia. However, adenosine\/MRPs-dependent chemoresistance under hypoxia has not been studied until now. Transcript and protein levels were determined by RT-qPCR and Western blot, respectively. MRP extrusion capacity was determined by intracellular 5 (6)-Carboxyfluorescein diacetate (CFDA) accumulation. Cell viability was measured by MTS assays. Cell cycle and apoptosis were determined by flow cytometry. Here, we show for the first time that MRP3 expression is induced under hypoxia through the A2B adenosine receptor. Hypoxia enhances MRP-dependent extrusion capacity and the chemoresistance of GSCs. Meanwhile, MRP3 knockdown decreases GSC viability under hypoxia. Downregulation of the A2B receptor decreases MRP3 expression and chemosensibilizes GSCs treated with teniposide under hypoxia. These data suggest that hypoxia-dependent activation of A2B adenosine receptor promotes survival of GSCs through MRP3 induction.<\/jats:p>","DOI":"10.3390\/ijms23169022","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T01:47:21Z","timestamp":1660528041000},"page":"9022","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A2B Adenosine Receptor Enhances Chemoresistance of Glioblastoma Stem-Like Cells under Hypoxia: New Insights into MRP3 Transporter Function"],"prefix":"10.3390","volume":"23","author":[{"given":"Jos\u00e9-Dellis","family":"Rocha","sequence":"first","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5110566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Uribe","sequence":"additional","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5110566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javiera","family":"Delgado","sequence":"additional","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5110566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1857-8698","authenticated-orcid":false,"given":"Ignacio","family":"Niechi","sequence":"additional","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5110566, Chile"},{"name":"Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8413-8028","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Alarc\u00f3n","sequence":"additional","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5110566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Ignacio","family":"Erices","sequence":"additional","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5110566, Chile"},{"name":"Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00f3mulo","family":"Melo","sequence":"additional","affiliation":[{"name":"Servicio de Neurocirug\u00eda, Instituto de Neurocirug\u00eda Dr. Asenjo, Santiago 7500691, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9448-2028","authenticated-orcid":false,"given":"Rodrigo","family":"Fern\u00e1ndez-Gajardo","sequence":"additional","affiliation":[{"name":"Servicio de Neurocirug\u00eda, Instituto de Neurocirug\u00eda Dr. Asenjo, Santiago 7500691, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1848-5697","authenticated-orcid":false,"given":"Flavio","family":"Salazar-Onfray","sequence":"additional","affiliation":[{"name":"Instituto de Ciencias Biom\u00e9dicas, Facultad de Medicina, Universidad de Chile, Santiago 7500691, Chile"},{"name":"Millennium Institute on Immunology and Immunotherapy, Facultad de Medicina, Universidad de Chile, Santiago 7500691, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rody","family":"San Mart\u00edn","sequence":"additional","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5110566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Quezada Monr\u00e1s","sequence":"additional","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5110566, Chile"},{"name":"Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1002\/ijc.24408","article-title":"Tumor microvasculature supports proliferation and expansion of glioma-propagating cells","volume":"125","author":"Borovski","year":"2009","journal-title":"Int. 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