title: Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells.
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 3beta, GSK-3beta, 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-3beta levels in IB-MECA treated melanoma cells. This observation suggests that the treatment of cells with IB-MECA augments the activity of GSK-3beta in the cells. Evaluation of beta-catenin, a key component of Wnt signaling pathway which, upon phosphorylation by GSK-3beta rapidly ubiquitinates, showed a substantial decrease in its level after IB-MECA treatment. Accordingly, the level of beta-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-3beta and beta-catenin in the anti-tumor activity of A3AR agonists.
authors.affiliation: Laboratory of Clinical and Tumor Immunology, The Felsenstein Medical Research Center, Tel Aviv University, Sackler Faculty of Medicine, Rabin Medical Center, Petach-Tikva 49100, Israel. pfishman@post.tau.ac.il
authors.forename: Pnina
authors.initials: P
authors.lastname: Fishman
authors.forename: Lea
authors.initials: L
authors.lastname: Madi
authors.forename: Sara
authors.initials: S
authors.lastname: Bar-Yehuda
authors.forename: Faina
authors.initials: F
authors.lastname: Barer
authors.forename: Luis
authors.initials: L
authors.lastname: Del Valle
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D058906:Purinergic P1 Receptor Agonists; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D025801:Ubiquitin; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D016213:Cyclins; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D058906:Purinergic P1 Receptor Agonists; D015534:Trans-Activators; D025801:Ubiquitin; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D000242:Cyclic AMP; D038341:Glycogen Synthase Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000241:Adenosine