title: 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.
abstract: Adenosine exerts its effects through four subtypes of G-protein-coupled receptors: A(1), A(2A), A(2B), and A(3). Stimulation of the human A(3) 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 A(3) 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 A(1), A(2A), or A(2B) receptor antagonists, although it was abolished by A(3) receptor antagonists. Furthermore, the response to Cl-IB-MECA was generated at the cell surface, since the inhibition of A(3) receptor expression, by using small interfering RNA, abolished agonist effects. Using A375 cells, we show that A(3) 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.
authors.affiliation: Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Merighi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Benini
authors.forename: Prisco
authors.initials: P
authors.lastname: Mirandola
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Edward
authors.initials: E
authors.lastname: Leung
authors.forename: Stephen
authors.initials: S
authors.lastname: Maclennan
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000235:genetics; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000241:Adenosine; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D043684:Receptor, Adenosine A3; C494918:AKT1 protein, human; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide