title: Inhibition of protein kinase CK2 by CX-5011 counteracts imatinib-resistance preventing rpS6 phosphorylation in chronic myeloid leukaemia cells: new combined therapeutic strategies.
abstract: Chronic myeloid leukaemia (CML) is a myeloproliferative disorder promoted by the constitutive tyrosine kinase activity of Bcr-Abl oncoprotein. Although treatment with the Bcr-Abl-inhibitor imatinib represents the first-line therapy against CML, almost 20-30% of patients develop chemotherapeutic resistance and require alternative therapy. Here we show that a strong hyper-phosphorylation/activation of ERK1/2, Akt Ser473, and 40S ribosomal protein S6 (rpS6) is detectable in imatinib-resistant KCL22 and K562 CML cells as compared to the -sensitive cell variants. In imatinib-resistant CML cells, high concentration of imatinib is required to strongly inhibit Bcr-Abl, ERK1/2 and Akt Ser473 phosphorylation, but under these conditions the phosphorylation of rpS6, a common downstream effector of MEK/ERK1/2 and PI3K/Akt/mTOR pathways is only slightly reduced. By contrast, down-regulation of the protein kinase CK2 by the inhibitor CX-5011 or by silencing the CK2 subunits does not affect the activation state of MEK/ERK1/2 or PI3K/Akt/mTOR signalling, but causes a drop in rpS6 phosphorylation in parallel with reduced protein synthesis. CK2-inhibition by CX-5011 induces cell death by apoptosis and acts synergistically with imatinib or the MEK-inhibitor U0126 in reducing the viability of imatinib-resistant CML cells. The ternary mixture containing CX-5011, imatinib and U0126 represents the most effective synergistic combination to counteract CML cell viability. These results disclose a novel CK2-mediated mechanism of acquired imatinib-resistance resulting in hyper-phosphorylation of rpS6. We suggest that co-targeting CK2 and MEK protein kinases is a promising strategy to restore responsiveness of resistant CML cells to imatinib.
authors.affiliation: Department of Biomedical Sciences and CNR Institute of NeuroSciences, University of Padova, 35131 Padova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Salizzato
authors.affiliation: Department of Biomedical Sciences and CNR Institute of NeuroSciences, University of Padova, 35131 Padova, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Borgo
authors.affiliation: Department of Biomedical Sciences and CNR Institute of NeuroSciences, University of Padova, 35131 Padova, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Cesaro
authors.affiliation: Department of Biomedical Sciences and CNR Institute of NeuroSciences, University of Padova, 35131 Padova, Italy.
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
authors.affiliation: Department of Biomedical Sciences and CNR Institute of NeuroSciences, University of Padova, 35131 Padova, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Donella-Deana
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D038601:Ribosomal Protein S6 / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C568365:5-(3-ethynylphenylamino)pyrimido(4,5-c)quinoline-8-carboxylic acid; D000970:Antineoplastic Agents; D002070:Butadienes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D034741:RNA, Small Interfering; D038601:Ribosomal Protein S6; C113580:U 0126; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: CX-5011; chronic myeloid leukaemia; imatinib-resistance; protein kinase CK2; rpS6