Adenosine exerts its effects through four subtypes of G-protein-coupled receptors: A1, A2A, A2B, and A3. Stimulation of the human A3 receptor has been suggested to influence cell death and proliferation. The phosphatidylinositide- 3-OH kinase (PI3K)/Akt and the Raf/mitogen- activated protein kinase (MAPK/ERK) kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways have central roles in the regulation of cell survival and proliferation. Due to their importance, the cross-talk between these two pathways has been investigated. Here, we show that the A3 adenosine receptor agonist Cl-IB-MECA stimulates PI3K-dependent phosphorylation of Akt leading to the reduction of basal levels of ERK1/2 phosphorylation, which in turn inhibits cell proliferation. The response to Cl-IB-MECA was not blocked by A1, A2A, or A2B receptor antagonists, although it was abolished by A3 receptor antagonists. Furthermore, the response to Cl-IB-MECA was generated at the cell surface, since the inhibition of A3 receptor expression, by using small interfering RNA, abolished agonist effects. Using A375 cells, we show that A3 adenosine receptor stimulation results in PI3Kdependent phosphorylation of Akt, leading to the reduction of basal levels of ERK1/2 phosphorylation, which in turn inhibits cell proliferation.
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