Oncotarget

Research Papers:

Inhibition of protein kinase CK2 by CX-5011 counteracts imatinib-resistance preventing rpS6 phosphorylation in chronic myeloid leukaemia cells: new combined therapeutic strategies

Valentina Salizzato _, Christian Borgo, Luca Cesaro, Lorenzo A. Pinna and Arianna Donella-Deana

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Oncotarget. 2016; 7:18204-18218. https://doi.org/10.18632/oncotarget.7569

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Abstract

Valentina Salizzato1, Christian Borgo1, Luca Cesaro1, Lorenzo A. Pinna1, Arianna Donella-Deana1

1Department of Biomedical Sciences and CNR Institute of NeuroSciences, University of Padova, 35131 Padova, Italy

Correspondence to:

Arianna Donella-Deana, e-mail: arianna.donella@unipd.it

Keywords: chronic myeloid leukaemia, imatinib-resistance, protein kinase CK2, rpS6, CX-5011

Received: November 03, 2015    Accepted: February 11, 2016    Published: February 22, 2016

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.


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