title: Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells.
abstract: Adenosine displays contradictory effects on cell growth: it improves cell proliferation, but it may also induce apoptosis and impair cell survival. Following the pharmacologic characterization of adenosine receptor expression on the human melanoma cell line A375, we chose A375 as our cellular model to define how the extracellular adenosine signals are conveyed from each receptor. By using selective adenosine receptor agonists or antagonists, we found that A2A stimulation reduced cell viability and cell clone formation, whereas, at the same time, it improved cell proliferation. In support of this finding we demonstrated that the stimulation of A2A adenosine receptors stably expressed in Chinese hamster ovary cell clone reproduced deleterious effects observed in human melanoma cells. A3 stimulation counteracted A2A-induced cell death but also reduced cell proliferation. Furthermore, we found that A3 stimulation ensures cell survival. We demonstrated that adenosine triggers a survival signal via A3 receptor activation and it kills the cell through A2A receptor inducing a signaling pathway that involves protein kinase C and mitogen-activated protein kinases.
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: Prisco
authors.initials: P
authors.lastname: Mirandola
authors.forename: Daniela
authors.initials: D
authors.lastname: Milani
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
authors.forename: Edward
authors.initials: E
authors.lastname: Leung
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016466:CHO Cells; D002455:Cell Division; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000241:Adenosine