Aberrant signalling by protein kinase CK2 in imatinib-resistant chronic myeloid leukaemia cells: biochemical evidence and therapeutic perspectives

Mol Oncol. 2013 Dec;7(6):1103-15. doi: 10.1016/j.molonc.2013.08.006. Epub 2013 Aug 22.

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.

Keywords: Bcr-Abl; CK2; Chronic myeloid leukaemia; Imatinib-resistance; Inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Benzamides / pharmacology*
  • Casein Kinase II / antagonists & inhibitors
  • Casein Kinase II / genetics
  • Casein Kinase II / metabolism*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Imatinib Mesylate
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Naphthyridines / pharmacology
  • Phenazines
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrimidines / pharmacology*
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics

Substances

  • Antineoplastic Agents
  • Benzamides
  • Naphthyridines
  • Phenazines
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • silmitasertib
  • Fusion Proteins, bcr-abl
  • Casein Kinase II
  • Proto-Oncogene Proteins c-akt