Abstract
MRP1 transporter correlates positively with glioma malignancy and the Multiple Drug Resistance (MDR) phenotype in Glioblastoma Multiforme (GBM). Evidence shows that the MRP1 transporter is controlled by the adenosine signalling axis. The aim of this study was to identify the role of adenosine on the MDR phenotype in Glioblastoma Stem-like Cells (GSCs), the cell population responsible for the tumorigenic and chemoresistance capabilities of this tumour. We found that GSCs have increased intrinsic capacity to generate extracellular adenosine, thus controlling MRP1 transporter expression and activity via activation of the adenosine A3 receptor (A3AR). We showed PI3K/Akt and MEK/ERK1/2 signaling pathways downstream A3AR to control MRP1 in GSCs. In vitro pharmacological blockade of A3AR had a chemosensitizing effect, enhancing the actions of antitumour drugs and decreasing cell viability and proliferation of GSCs. In addition, we produced an in vivo xenograft model by subcutaneous inoculation of human GSCs in NOD/SCID-IL2Rg null mice. Pharmacological blockade of A3AR generated a chemosensitizing effect, enhancing the effectiveness of the MRP1 transporter substrate, vincristine, reducing tumour size and the levels of CD44 and Nestin stem cell markers as well as the Ki-67 proliferation indicator. In conclusion, we demonstrated the chemosensitizing effect of A3AR blockade on GSCs.
Highlights
Glioblastoma Multiforme (GBM), classified as a grade IV astrocytoma by the World Health Organization (WHO), is considered the most common and aggressive tumour of the Central Nervous System (CNS) [1, 2]
When maintained in serum-free neurobasal medium, human GBM Primary Culture (PC) cells and the human U87MG cell line were capable of forming non-adherent cell clusters or neurospheres, a cell subpopulation enriched in Glioblastoma Stem-like Cells (GSCs) (Supplementary Figure S1)
Immunocytochemistry staining of GSCs derived from U87MG and Primary Cultures (PC) cells showed expression of Stem Cell markers CD44 and Nestin (Supplementary Figure S1A)
Summary
Glioblastoma Multiforme (GBM), classified as a grade IV astrocytoma by the World Health Organization (WHO), is considered the most common and aggressive tumour of the Central Nervous System (CNS) [1, 2]. Anti-angiogenic agents, and more recently immunotherapeutic approaches, are being developed to improve GBM prognostics [3, 4]. Since it is a highly infiltrative tumour, cancer cells often invade healthy brain tissue and evade surgical resection which inevitably leads to early reoccurrence [5]. Acquisition of the MDR phenotype correlates with overexpression of members from the ATP-binding cassette (ABC) transporter superfamily [7] These www.impactjournals.com/oncotarget transporters are efflux pumps that translocate a wide range of substrates, such as lipophilic and xenobiotic molecules, to the extracellular environment using energy from ATP hydrolysis [7]. Inhibition of MRP1 activity increases cell sensitivity to cytotoxic and antiproliferative effects of antineoplastic drugs such as vincristine, etoposide and taxol [8], representing a possible therapeutic target to control GBM reoccurrence
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