TY - JOUR
T1 - Activation of the A3 adenosine receptor affects cell cycle progression and cell growth
AU - Brambilla, Roberta
AU - Cattabeni, Flamino
AU - Ceruti, Stefania
AU - Barbieri, Daniela
AU - Franceschi, Claudio
AU - Kim, Yong Chul
AU - Jacobson, Kenneth A.
AU - Klotz, Karl Norbert
AU - Lohse, Martin J.
AU - Abbracchio, Maria P.
PY - 2000
Y1 - 2000
N2 - The A3 adenosine receptor has been implicated in modulation of cell growth. As a first step to the characterization of the underlying mechanisms, we exposed Chinese hamster ovary (CHO) cells transfected with the human A3 receptor (A3R-CHO) to selective A3 receptor ligands. At micromolar concentrations, the A3 agonists N6-(3-iodobenzyl)-adenosine-5'-N- methyluronamide (IB-MECA) and its 2-chloro derivative Cl-IB-MECA reduced cell number, with no effects on either parental CHO cells (not expressing any adenosine receptor), or CHO cells transfected with the human A1 receptor. Cl-IB-MECA also reduced cell number in the human HEK293 cell line transfected with the human A3 receptor cDNA as opposed to the respective untransfected wild-type cells. In A3R-CHO, agonist-induced effects were antagonized by nanomolar concentrations of A3 antagonists, including the triazoloquinazoline derivative MRS1220, the dihydropyridine derivative MRS1191, and the triazolonaphthyridine derivative L-249,313. A3 agonist- induced effects were not due to modulation of cell adhesion, nor to necrosis or apoptosis. Growth curves revealed highly impeded growth, and flow- cytometric analysis showed markedly reduced bromodeoxyuridine incorporation into nuclei. The effect on cell cycle was completely antagonized by MRS1191. Hence, activation of the human A3 receptor in A3R-CHO results in markedly impaired cell cycle progression, suggesting an important role for this adenosine receptor subtype in cell cycle regulation and cell growth.
AB - The A3 adenosine receptor has been implicated in modulation of cell growth. As a first step to the characterization of the underlying mechanisms, we exposed Chinese hamster ovary (CHO) cells transfected with the human A3 receptor (A3R-CHO) to selective A3 receptor ligands. At micromolar concentrations, the A3 agonists N6-(3-iodobenzyl)-adenosine-5'-N- methyluronamide (IB-MECA) and its 2-chloro derivative Cl-IB-MECA reduced cell number, with no effects on either parental CHO cells (not expressing any adenosine receptor), or CHO cells transfected with the human A1 receptor. Cl-IB-MECA also reduced cell number in the human HEK293 cell line transfected with the human A3 receptor cDNA as opposed to the respective untransfected wild-type cells. In A3R-CHO, agonist-induced effects were antagonized by nanomolar concentrations of A3 antagonists, including the triazoloquinazoline derivative MRS1220, the dihydropyridine derivative MRS1191, and the triazolonaphthyridine derivative L-249,313. A3 agonist- induced effects were not due to modulation of cell adhesion, nor to necrosis or apoptosis. Growth curves revealed highly impeded growth, and flow- cytometric analysis showed markedly reduced bromodeoxyuridine incorporation into nuclei. The effect on cell cycle was completely antagonized by MRS1191. Hence, activation of the human A3 receptor in A3R-CHO results in markedly impaired cell cycle progression, suggesting an important role for this adenosine receptor subtype in cell cycle regulation and cell growth.
KW - Adenosine
KW - Adenosine receptor
KW - Cell cycle
KW - Cell growth modulation
KW - CHO transfected cells
KW - HEK293 transfected cells
KW - Human A
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U2 - 10.1007/s002109900186
DO - 10.1007/s002109900186
M3 - Article
C2 - 10731034
AN - SCOPUS:0033624772
VL - 361
SP - 225
EP - 234
JO - Naunyn-Schmiedeberg's Archives of Pharmacology
JF - Naunyn-Schmiedeberg's Archives of Pharmacology
SN - 0028-1298
IS - 3
ER -