Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells

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Abstract
The A3 adenosine receptor, A3AR, belongs to the family of Gi proteins, which upon induction, suppresses the formation of cAMP and its downstream effectors. Recent studies have indicated that activation of A3AR by its agonist, IB-MECA, results in growth inhibition of malignant cells. Here we demonstrate the ability of IB-MECA to decrease the levels of protein kinase A, a downstream effector of cAMP, and protein kinase B/Akt in melanoma cells. Examination of glycogen synthase kinase 3β, GSK-3β, whose phosphorylation is controlled by protein kinase A and B, showed a substantial decrease in the levels of its phosphorylated form and an increase in total GSK-3β levels in IB-MECA treated melanoma cells. This observation suggests that the treatment of cells with IB-MECA augments the activity of GSK-3β in the cells. Evaluation of β-catenin, a key component of Wnt signaling pathway which, upon phosphorylation by GSK-3β rapidly ubiquitinates, showed a substantial decrease in its level after IB-MECA treatment. Accordingly, the level of β-catenin responsive cell growth regulatory genes including c-myc and cyclin D1 was severely declined upon treatment of the cells with IB-MECA. These observations which link cAMP to the Wnt signaling pathway provide mechanistic evidence for the involvement of Wnt pathway via its key elements GSK-3β and β-catenin in the anti-tumor activity of A3AR agonists.