5′‐ectonucleotidase mediates multiple‐drug resistance in glioblastoma multiforme cells

Abstract

Glioblastoma multiforme (GBM) cells are characterised by their extreme chemoresistance. The activity of multiple-drug resistance (MDR) transporters that extrude antitumor drugs from cells plays the most important role in this phenomenon. To date, the mechanism controlling the expression and activity of MDR transporters is poorly understood. Activity of the enzyme ecto-5 0 -nucleotidase (CD73) in tumor cells, which hydrolyses AMP to adenosine, has been linked to immunosuppression and prometastatic effects in breast cancer and to the proliferation of glioma cells. In this study, we identify a high expression of CD73 in surgically resected samples of human GBM. In primary cultures of GBM, inhibition of CD73 activity or knocking down its expression by siRNA reversed the MDR phenotype and cell viability was decreased up to 60% on exposure to the antitumoral drug vincristine. This GBM chemosensitization was caused by a decrease in the expression and activity of the multiple drug associated protein 1 (Mrp1), the most important transporter conferring multiple drug resistance in these cells. Using pharmacological modulators, we have recognized the adenosine A 3 receptor subtype in mediation of the chemoresistant phenotype in these cells. In conclusion, we have determined that the activity of CD73 to trigger adenosine signaling sustains chemoresistant phenotype in GBM cells. ORIGINAL RESEARCH ARTICLE 602 J o u r n a l o f J o u r n a l o f Cellular Physiology Cellular Physiology ß 2 0 1 2 W I L E Y P E R I O D I C A L S , I N C .

Anti-CD73 in Cancer Immunotherapy: Awakening New Opportunities

“…Pre-clinical[20, 138-140] and clinical studies [24, 141] indicate that CD73 has an important role in modulating anti-cancer chemoresistance mechanisms. Recent studies reported the involvement of CD73 in vincristine resistant glioblastoma multiforme cells[20], where a tight correlation between CD73 and the multiple drug protein-1 (Mrp1) (a transporter involved in conferring multiple drug resistance to cancer cells) was observed. The inhibition of CD73 expression in glioblastoma multiforme cells reduced Mrp1 expression, indicating that increased expression of CD73 can mediate drug resistance via Mrp1 modulation[139].…”

NTPDase3 and ecto-5′-nucleotidase/CD73 are differentially expressed during mouse bladder cancer progression

“…Furthermore, ecto-5′-NT/CD73 overexpression promotes invasion, migration, adhesion, and metastasis of human breast cancer cells [20,57], indicating higher invasiveness and metastatic capability to melanomas [56,58] and poor prognosis in human colorectal cancer [22]. Ecto-5′-NT/CD73 expression in cancer cells has been also linked with drug resistance [26,59] and immune escape [44,60]. Moreover, researchers have already targeted ecto-5′-NT/ CD73 in an attempt to develop promising therapies, for instance, ecto-5′-NT/CD73 inhibitors have shown antiproliferative effects in bladder cancer cell lines and gliomas [61,62], and decrease in ovarian cancer progression [63].…”

“…This enzyme is highly expressed in a variety of solid tumors [19][20][21][22] and has both its enzymatic activity and its adhesion protein function associated with cancer progression [23,24]. Besides, ecto-5′-NT/CD73 was found to be involved in cancer cell growth, maturation, differentiation, adhesion, migration, invasiveness, metastasis, immune escape, and drug resistance [19,[21][22][23][24][25][26][27].…”

Biological Therapy of Cancer

“…The high concentration of adenosine produced by the CD73 on glioblastoma multiforme triggers an adenosine signaling that induces the multidrug resistance phenotype characteristic of this tumor. 49 Inhibition of Treg tumoral homing may be achieved by blocking the selective recruitment and retention of Tregs at tumor sites through the interaction of some chemokine receptors and the protein CCL22, which is secreted by DCs and macrophages. Finally, exploitation of T-cell plasticity may be achieved by modulating IL-6, TGF-β, and PGE2 expression, as occurs with the COX-2 inhibitor celecoxib.…”