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Indomethacin stimulates activity and expression of ecto-5'-nucleotidase/CD73 in glioma cell lines
Andressa Bernardi1, Luci Bavaresco, Márcia R Wink
1Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Av. Ramiro Barcelos, 2600-anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
Abstract:
Gliomas are the most common and devastating primary tumors of the central nervous system. Ecto-NTPDases and ecto-5'-nucleotidase/CD73 can control extracellular ATP/adenosine levels, which have been described as proliferation factors. Here, we investigate the influence of indomethacin on the enzyme cascade that catalyses the interconversion of purine nucleotides in U138-MG and C6 glioma cell lines. Exposure of glioma cells to 100 microM indomethacin for 48 h caused increases of 52% (P < 0.05) and 62% (P < 0.05) in the AMP hydrolysis rate in C6 and U138-MG cell lines, respectively. Indomethacin treatments also increased ATP hydrolysis. Significant increase in ecto-5'-nucleotidase/CD73 mRNA and protein levels were observed after treatment with indomethacin. Pretreatment of glioma cells with a specific antagonist of the adenosine A(3) receptor, MRS1220 (1 microM; 9-Chloro-2-(2-furanyl)-5-((phenylacetyl)amino)-[1,2,4]triazolo[1,5-c]quinazoline), significantly reduced the inhibition of cell proliferation induced by indomethacin. In addition, a significant increase in mRNA levels of the adenosine A(3) receptor was observed after treatment with indomethacin. In conclusion, our data indicate that adenosine A(3) receptors and the enzyme, ecto-5'-nucleotidase/CD73, are involved in the anti-proliferative effect of indomethacin in glioma cells.
Insights
Indomethacin inhibits glioma cell proliferation by increasing ecto-5'-nucleotidase/CD73 activity and adenosine A(3) receptor levels. These changes in purine metabolism are key to its anti-proliferative effects in glioma.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Pharmacology
Background:
- Gliomas are aggressive primary central nervous system tumors.
- Extracellular ATP and adenosine regulate glioma cell proliferation.
- Ecto-nucleotidases, including ecto-5 extprime-nucleotidase/CD73, modulate these extracellular nucleotides.
Purpose of the Study:
- To investigate the effects of indomethacin on purine nucleotide metabolism in glioma cells.
- To elucidate the role of ecto-5 extprime-nucleotidase/CD73 and adenosine A(3) receptors in indomethacin's anti-proliferative action.
Main Methods:
- U138-MG and C6 glioma cell lines were treated with indomethacin (100 microM for 48 h).
- Enzyme activity assays measured AMP and ATP hydrolysis rates.
- Quantitative PCR and Western blotting assessed ecto-5 extprime-nucleotidase/CD73 and adenosine A(3) receptor expression.
- Cell proliferation was evaluated with and without indomethacin and an adenosine A(3) receptor antagonist (MRS1220).
Main Results:
- Indomethacin significantly increased AMP and ATP hydrolysis rates in both cell lines.
- Ecto-5 extprime-nucleotidase/CD73 mRNA and protein levels were elevated by indomethacin.
- Indomethacin treatment upregulated adenosine A(3) receptor mRNA expression.
- Blocking adenosine A(3) receptors with MRS1220 partially reversed indomethacin's inhibition of cell proliferation.
Conclusions:
- Indomethacin enhances ecto-5 extprime-nucleotidase/CD73 activity and increases adenosine A(3) receptor expression in glioma cells.
- Adenosine A(3) receptors are implicated in mediating the anti-proliferative effects of indomethacin.
- Targeting these pathways may offer novel therapeutic strategies for glioma treatment.
