Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells

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 A(2A) 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 A(2A) adenosine receptors stably expressed in Chinese hamster ovary cell clone reproduced deleterious effects observed in human melanoma cells. A(3) stimulation counteracted A(2A)-induced cell death but also reduced cell proliferation. Furthermore, we found that A(3) stimulation ensures cell survival. We demonstrated that adenosine triggers a survival signal via A(3) receptor activation and it kills the cell through A(2A) receptor inducing a signaling pathway that involves protein kinase C and mitogen-activated protein kinases.