Indomethacin stimulates activity and expression of ecto-5'-nucleotidase/CD73 in glioma cell lines.
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.
Bernardi
Andressa
A
Departamento 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.
Bavaresco
Luci
L
Wink
Márcia R
MR
Jacques-Silva
Maria C
MC
Delgado-Cañedo
Andrés
A
Lenz
Guido
G
Battastini
Ana M O
AM
D015720:5'-Nucleotidase / Q000235:genetics* / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
C110041:9-chloro-2-(2-furyl)-5-phenylacetylamino(1,2,4)triazolo(1,5-c)quinazoline; D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D012333:RNA, Messenger; D014230:Triazoles; D014970:Xanthines; C053907:8-cyclopentyl-1,3-dimethylxanthine; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D015720:5'-Nucleotidase; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D007213:Indomethacin; D004121:Dimethyl Sulfoxide