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Pharmacological inhibition of protein kinase CK2 reverts the multidrug resistance phenotype of a CEM cell line characterized by high CK2 level

Oncogene volume 26, pages 6915–6926 (2007)Cite this article

Abstract

Protein kinase CK2 is an ubiquitous and constitutively active kinase, which phosphorylates many cellular proteins and is implicated in the regulation of cell survival, proliferation and transformation. We investigated its possible involvement in the multidrug resistance phenotype (MDR) by analysing its level in two variants of CEM cells, namely S-CEM and R-CEM, normally sensitive or resistant to chemical apoptosis, respectively. We found that, while the CK2 regulatory subunit β was equally expressed in the two cell variants, CK2α catalytic subunit was higher in R-CEM and this was accompanied by a higher phosphorylation of endogenous protein substrates. Pharmacological downregulation of CK2 activity by a panel of specific inhibitors, or knockdown of CK2α expression by RNA interference, were able to induce cell death in R-CEM. CK2 inhibitors could promote an increased uptake of chemotherapeutic drugs inside the cells and sensitize them to drug-induced apoptosis in a co-operative manner. CK2 blockade was also effective in inducing cell death of a different MDR line (U2OS). We therefore conclude that inhibition of CK2 can be considered as a promising tool to revert the MDR phenotype.

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Abbreviations

2a:

2-amino-4,5,6,7-tetrabromo-1H-benzimidazole

CK2:

casein kinase 2

IQA:

5-oxo-5,6-dihydroindolo-(1,2-a)quinazolin-7-yl]acetic acid

MDR:

multidrug resistance

MNA:

1,8-dihydroxy-4-nitro-anthracene-9,10-dione

MNX:

1,8-dihydroxy-4-nitro-xanthen-9-one

MTT:

3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltriazolium bromide

P-gp:

P-glycoprotein

R-CEM:

multidrug resistant CEM

S-CEM:

wild type CEM

siRNA:

short interference RNA

TBB:

4,5,6,7-tetrabromobenzotriazole

TBI:

4,5,6,7-tetrabromobenzimidazole

Vbl:

vinblastine

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Acknowledgements

We thank Dr S Sarno (Padova) for providing recombinant CK2, and Dr S Klumpp (Munster) for providing anti Tp117-BAD. The work was supported by grants from University of Padova (Progetto Ateneo 2005) to MR and from AIRC and EC (PRO-KINASERESEARCH 503467) to LAP.

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Authors and Affiliations

  1. Department of Biological Chemistry and CNR Neuroscience Institute, University of Padova, Padova, Italy

    G Di Maira, F Brustolon, K Tosoni, L A Pinna & M Ruzzene

  2. VIMM (Venetian Institute of Molecular Medicine), Padova, Italy

    G Di Maira, F Brustolon, K Tosoni, L A Pinna & M Ruzzene

  3. Department of Anatomy and Histology, University of Modena and Reggio Emilia, Modena, Italy

    J Bertacchini & S Marmiroli

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  1. G Di Maira
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  2. F Brustolon
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  6. L A Pinna
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Correspondence to M Ruzzene.

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Di Maira, G., Brustolon, F., Bertacchini, J. et al. Pharmacological inhibition of protein kinase CK2 reverts the multidrug resistance phenotype of a CEM cell line characterized by high CK2 level. Oncogene 26, 6915–6926 (2007). https://doi.org/10.1038/sj.onc.1210495

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