The role of ecto-5′-nucleotidase/CD73 in glioma cell line proliferation

Abstract

Malignant gliomas are the most common and devastating primary tumors in the brain and, despite treatment, patients with these tumors have a poor prognosis. The participation of ecto-5'-NT/CD73 per se as a proliferative factor, being involved in the control of cell growth, differentiation, invasion, migration and metastasis processes has been previously proposed. In the present study, we evaluated the activity and functions of ecto-5'-NT/CD73 during the proliferation process of rat C6 and human U138MG glioma cell lines. Increasing confluences and culture times led to an increase in ecto-5'-NT/CD73 activity in both C6 and U138MG glioma cells. RT-PCR analysis and flow cytometry analysis showed a significant increase in ecto-5'-NT/CD73 mRNA and protein levels, respectively, comparing confluent with sub-confluent cultures in human U138MG glioma cells. Ecto-5'-nucleotidase/CD73 may regulate the extracellular adenosine 5'-monophosphate (AMP) and adenosine levels. Treatment with 1 microM APCP, a competitive ecto-5'-NT/CD73 inhibitor, caused a significant reduction of 30% in glioma cell proliferation. In addition, 100 microM adenosine increases cell proliferation by 36%, and the treatment with adenosine plus NBTI and dipyridamole, produced an additional and significant increase of on cell proliferation. The inhibitory effect on cell proliferation caused by APCP was reverted by co-treatment with NBTI and dipyridamole. AMP (1 mM and 3 mM) decreased U138MG glioma cell proliferation by 29% and 42%, respectively. Taken together, these results suggest the participation of ecto-5'-NT/CD73 in cell proliferation and that this process is dependent upon the enzyme's production of adenosine, a proliferative factor, and removal of AMP, a toxic molecule for gliomas.

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

“…These findings indicate that this enzyme is involved in bladder cancer progression, and makes it a promissory therapeutic target to local treatments by instillation of inhibitors of this enzyme. This result is in agreement with the literature that shows the increase of ecto-5′-NT/CD73 expression in many other cancers such as breast cancer, glioma, and melanoma [19,23,56]. 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].…”

“…The final dephosphorylation of nucleotides, conversion of nucleoside monophosphates (e.g., AMP) to their respective nucleosides (e.g., adenosine), is catalyzed by ecto-5′-nucleotidase/CD73 (ecto-5′-NT/CD73). 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].…”

Extracellular adenosine triphosphate and adenosine in cancer

“…CD73 on cancer cells. CD73 has been found to be overexpressed in several types of cancer, including bladder cancer (Stella et al, 2010), leukemia (Mikhailov et al, 2008), glioma (Bavaresco et al, 2008), glioblastoma (Ludwig et al, 1999), melanoma (Sadej et al, 2006), ovarian cancer (Jin et al, 2010), thyroid cancer (Kondo et al, 2006), esophageal cancer (Fukuda et al, 2004), gastric cancer (Durak et al, 1994), colon cancer (Eroglu et al, 2000), prostate cancer and breast cancer . Notably, CD73 expression has been associated with a pro-metastatic phenotype in melanoma and breast cancer (Lee et al, 2003;LethLarsen et al, 2009).…”

CD73 promotes tumor growth and metastasis

“…In addition to the immunoregulatory roles of CD73, the participation of CD73 per se as a proliferative factor, being involved in the control of cell growth, differentiation, invasion, migration and metastasis processes has been established. 10,11 Moreover, CD73-derived adenosine can directly enhance tumor cell adhesion 7,8 and/or chemotaxis. 19 It is also intriguing that CD73 may contribute to tumor angiogenesis.…”