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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2013

Open Access 01-12-2013 | Research

Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity

Authors: Laura Quotti Tubi, Carmela Gurrieri, Alessandra Brancalion, Laura Bonaldi, Roberta Bertorelle, Sabrina Manni, Laura Pavan, Federica Lessi, Renato Zambello, Livio Trentin, Fausto Adami, Maria Ruzzene, Lorenzo A Pinna, Gianpietro Semenzato, Francesco Piazza

Published in: Journal of Hematology & Oncology | Issue 1/2013

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Abstract

Background

The involvement of protein kinase CK2 in sustaining cancer cell survival could have implications also in the resistance to conventional and unconventional therapies. Moreover, CK2 role in blood tumors is rapidly emerging and this kinase has been recognized as a potential therapeutic target. Phase I clinical trials with the oral small ATP-competitive CK2 inhibitor CX-4945 are currently ongoing in solid tumors and multiple myeloma.

Methods

We have analyzed the expression of CK2 in acute myeloid leukemia and its function in cell growth and in the response to the chemotherapeutic agent daunorubicin We employed acute myeloid leukemia cell lines and primary blasts from patients grouped according to the European LeukemiaNet risk classification. Cell survival, apoptosis and sensitivity to daunorubicin were assessed by different means. p53-dependent CK2-inhibition-induced apoptosis was investigated in p53 wild-type and mutant cells.

Results

CK2α was found highly expressed in the majority of samples across the different acute myeloid leukemia prognostic subgroups as compared to normal CD34+ hematopoietic and bone marrow cells. Inhibition of CK2 with CX-4945, K27 or siRNAs caused a p53-dependent acute myeloid leukemia cell apoptosis. CK2 inhibition was associated with a synergistic increase of the cytotoxic effects of daunorubicin. Baseline and daunorubicin-induced STAT3 activation was hampered upon CK2 blockade.

Conclusions

These results suggest that CK2 is over expressed across the different acute myeloid leukemia subsets and acts as an important regulator of acute myeloid leukemia cell survival. CK2 negative regulation of the protein levels of tumor suppressor p53 and activation of the STAT3 anti-apoptotic pathway might antagonize apoptosis and could be involved in acute myeloid leukemia cell resistance to daunorubicin.
Appendix
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Metadata
Title
Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity
Authors
Laura Quotti Tubi
Carmela Gurrieri
Alessandra Brancalion
Laura Bonaldi
Roberta Bertorelle
Sabrina Manni
Laura Pavan
Federica Lessi
Renato Zambello
Livio Trentin
Fausto Adami
Maria Ruzzene
Lorenzo A Pinna
Gianpietro Semenzato
Francesco Piazza
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2013
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/1756-8722-6-78

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