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.

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

“…Moreover, we studied the effects of standard AR agonists and antagonists on lymphocyte proliferation. The results obtained from real-time PCR analysis showed expression for all four AR subtypes in the investigated cells, consistent with previous reports [22][23][24]39]. The adenosine A 2A receptor mRNA expression level was higher in PBL than in Jurkat T cells and was further upregulated after stimulation of the cells with PHA, as previously reported [40,41].…”

“…Furthermore, adenosine is able to stimulate cell growth and proliferation and/or to induce apoptosis in various normal and tumor cell lines. Proliferative or anti-proliferative effects appear to be dependent on the cell type, the distribution of adenosine receptor subtypes, and their expression on the cell surface [22][23][24][25]. A 3 adenosine receptors seem to play an important role [26][27][28], but recent evidence accumulates that A 2B ARs can be upregulated on malignant cells and are involved in the control of tumor growth and development [16,24,[29][30][31][32].…”

Adenosine receptors as therapeutic targets

“…Activation of the A 3 AR by adenosine triggers a cell survival response; by contrast, activation of A 2A ARs induces an apoptotic signalling pathway that involves protein kinase C and MAPKs 199 . Overexpression of the A 3 AR in transgenic mice resulted in embryonic lethality 141 , suggesting the possible use of selective A 3 AR agonists in anticancer therapy.…”

Normalization of A2A and A3 adenosine receptor up‐regulation in rheumatoid arthritis patients by treatment with anti–tumor necrosis factor α but not methotrexate

“…Cells were then lysed in Triton lysis buffer, and the protein concentration was determined using a bicinchoninic acid protein assay kit (Pierce, Rockford, IL). Aliquots Table 2. of total protein sample (50 g) were analyzed using antibodies specific for human A 2A and A 3 adenosine receptors (1 g/ml dilution; Alpha Diagnostic, San Antonio, TX) (40). Filters were washed and incubated for 1 hour at room temperature with peroxidase-conjugated secondary antibodies (1:2,000 dilution).…”