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J. Biol. Chem., Vol. 280, Issue 20, 19516-19526, May 20, 2005

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A₃ Adenosine Receptor Activation Inhibits Cell Proliferation via Phosphatidylinositol 3-Kinase/Akt-dependent Inhibition of the Extracellular Signal-regulated Kinase 1/2 Phosphorylation in A375 Human Melanoma Cells^*

Stefania Merighi, Annalisa Benini, Prisco Mirandola, Stefania Gessi, Katia Varani, Edward Leung¶, Stephen Maclennan¶, and Pier Andrea Borea||**

From the Department of Clinical and Experimental Medicine, Pharmacology Unit, and ^||Centro Nazionale di Eccellenza per lo Sviluppo di Metodologie Innovative per lo Studio ed il Trattamento delle Patologie Infiammatorie, University of Ferrara, Ferrara 44100, Italy, the Department of Human Anatomy, Pharmacology and Forensic Medicine, Institute of Normal Human Anatomy, Ospedale Maggiore, University of Parma, Parma 43100, Italy, ^¶King Pharmaceuticals, Cary, North Carolina 27513

Adenosine exerts its effects through four subtypes of G-protein-coupled receptors: A₁, A_2A, A_2B, 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, A_2A, or A_2B 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 PI3K-dependent phosphorylation of Akt, leading to the reduction of basal levels of ERK1/2 phosphorylation, which in turn inhibits cell proliferation.

Received for publication, December 7, 2004 , and in revised form, March 8, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Clinical and Experimental Medicine-Pharmacology Unit, 17-19 Via Fossato di Mortara, Ferrara 44100, Italy. Tel.: 39-0532-291214; Fax: 39-0532-291205; E-mail: bpa{at}dns.unife.it.

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