title: Aberrant signalling by protein kinase CK2 in imatinib-resistant chronic myeloid leukaemia cells: biochemical evidence and therapeutic perspectives.
abstract: Chronic myeloid leukaemia (CML) is driven by the fusion protein Bcr-Abl, a constitutively active tyrosine kinase playing a crucial role in initiation and maintenance of CML phenotype. Despite the great efficacy of the Bcr-Abl-specific inhibitor imatinib, resistance to this drug is recognized as a major problem in CML treatment. We found that in LAMA84 cells, characterized by imatinib-resistance caused by BCR-ABL1 gene amplification, the pro-survival protein kinase CK2 is up-regulated as compared to the sensitive cells. CK2 exhibits a higher protein-level and a parallel enhancement of catalytic activity. Consistently, CK2-catalysed phosphorylation of Akt-Ser129 is increased. CK2 co-localizes with Bcr-Abl in the cytoplasmic fraction as judged by subcellular fractionation and fluorescence immunolocalization. CK2 and Bcr-Abl are members of the same multi-protein complex(es) in imatinib-resistant cells as demonstrated by co-immunoprecipitation and co-sedimentation in glycerol gradients. Cell treatment with CX-4945, a CK2 inhibitor currently in clinical trials, counteracts CK2/Bcr-Abl interaction and causes cell death by apoptosis. Interestingly, combination of CX-4945 with imatinib displays a synergistic effect in reducing cell viability. Consistently, knockdown of CK2α expression by siRNA restores the sensitivity of resistant LAMA84 cells to low imatinib concentrations. Remarkably, the CK2/Bcr-Abl interaction and the sensitization towards imatinib obtained by CK2-inhibition in LAMA84 is observable also in other imatinib-resistant CML cell lines. These results demonstrate that CK2 contributes to strengthen the imatinib-resistance phenotype of CML cells conferring survival advantage against imatinib. We suggest that CK2 inhibition might be a promising tool for combined strategies in CML therapy.
authors.affiliation: Department of Biomedical Sciences, University of Padova and CNR Neuroscience Institute, Viale G. Colombo 3, 35131 Padova, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Borgo
authors.forename: Luca
authors.initials: L
authors.lastname: Cesaro
authors.forename: Valentina
authors.initials: V
authors.lastname: Salizzato
authors.forename: Maria
authors.initials: M
authors.lastname: Ruzzene
authors.forename: Maria Lina
authors.initials: ML
authors.lastname: Massimino
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
authors.forename: Arianna
authors.initials: A
authors.lastname: Donella-Deana
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009287:Naphthyridines / Q000494:pharmacology; D010619:Phenazines; D010879:Piperazines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009287:Naphthyridines; D010619:Phenazines; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C555142:silmitasertib; D016044:Fusion Proteins, bcr-abl; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt
keywords: Bcr-Abl; CK2; Chronic myeloid leukaemia; Imatinib-resistance; Inhibitor