کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2145621 | 1088806 | 2013 | 13 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Aberrant signalling by protein kinase CK2 in imatinib-resistant chronic myeloid leukaemia cells: Biochemical evidence and therapeutic perspectives Aberrant signalling by protein kinase CK2 in imatinib-resistant chronic myeloid leukaemia cells: Biochemical evidence and therapeutic perspectives](/preview/png/2145621.png)
• CK2 signalling is up-regulated in imatinib-resistant as compared to sensitive chronic myeloid leukaemia cells.
• CK2 and Bcr-Abl co-localise and are interacting proteins.
• Inhibition of CK2 causes cell death by apoptosis of chronic myeloid leukaemia cells.
• Down-regulation of CK2 signalling can overcome the imatinib-resistance.
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.
Journal: Molecular Oncology - Volume 7, Issue 6, December 2013, Pages 1103–1115