Protein kinase CK2 regulates AKT, NF-κB and STAT3 activation, stem cell viability and proliferation in acute myeloid leukemia

L Quotti Tubi; S Canovas Nunes; A Brancalion; E Doriguzzi Breatta; S Manni; E Mandato; F Zaffino; P Macaccaro; M Carrino; K Gianesin; L Trentin; G Binotto; R Zambello; G Semenzato; C Gurrieri; F Piazza

doi:10.1038/leu.2016.209

Protein kinase CK2 regulates AKT, NF-κB and STAT3 activation, stem cell viability and proliferation in acute myeloid leukemia

Leukemia. 2017 Feb;31(2):292-300. doi: 10.1038/leu.2016.209. Epub 2016 Aug 1.

Authors

L Quotti Tubi^{1

2}, S Canovas Nunes^{1

2}, A Brancalion^{1

2}, E Doriguzzi Breatta^{1

2}, S Manni^{1

2}, E Mandato^{1

2}, F Zaffino^{1

2}, P Macaccaro^{1

2}, M Carrino^{1

2}, K Gianesin^{1

2}, L Trentin^{1

2}, G Binotto¹, R Zambello^{1

2}, G Semenzato^{1

2}, C Gurrieri^{1

2}, F Piazza^{1

2}

Affiliations

¹ Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.
² Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.

PMID: 27479180
DOI: 10.1038/leu.2016.209

Abstract

Protein kinase CK2 sustains acute myeloid leukemia cell growth, but its role in leukemia stem cells is largely unknown. Here, we discovered that the CK2 catalytic α and regulatory β subunits are consistently expressed in leukemia stem cells isolated from acute myeloid leukemia patients and cell lines. CK2 inactivation with the selective inhibitor CX-4945 or RNA interference induced an accumulation of leukemia stem cells in the late S-G2-M phases of the cell cycle and triggered late-onset apoptosis. As a result, leukemia stem cells displayed an increased sensitivity to the chemotherapeutic agent doxorubicin. From a molecular standpoint, CK2 blockade was associated with a downmodulation of the stem cell-regulating protein BMI-1 and a marked impairment of AKT, nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, whereas FOXO3a nuclear activity was induced. Notably, combined CK2 and either NF-κB or STAT3 inhibition resulted in a superior cytotoxic effect on leukemia stem cells. This study suggests that CK2 blockade could be a rational approach to minimize the persistence of residual leukemia cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Adult
Aged
Aged, 80 and over
Antineoplastic Agents / pharmacology
Biomarkers
Casein Kinase II / antagonists & inhibitors
Casein Kinase II / genetics
Casein Kinase II / metabolism*
Cell Cycle / genetics
Cell Line, Tumor
Cell Proliferation
Cell Survival
Drug Resistance, Neoplasm / drug effects
Female
Forkhead Box Protein O3 / genetics
Forkhead Box Protein O3 / metabolism
Gene Expression
Humans
Immunophenotyping
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism*
Leukemia, Myeloid, Acute / pathology
Male
Middle Aged
NF-kappa B / metabolism*
Neoplastic Stem Cells / metabolism*
Polycomb Repressive Complex 1 / genetics
Polycomb Repressive Complex 1 / metabolism
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / metabolism*
STAT3 Transcription Factor / metabolism*
Signal Transduction

Substances

Antineoplastic Agents
Biomarkers
FOXO3 protein, human
Forkhead Box Protein O3
NF-kappa B
Protein Kinase Inhibitors
STAT3 Transcription Factor
Adenosine Triphosphate
Polycomb Repressive Complex 1
Casein Kinase II
Proto-Oncogene Proteins c-akt