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

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.

• Authors: 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
• Journal: Leukemia (Leukemia) Vol. 31 Issue 2 Pg. 292-300 (02 2017) ISSN: 1476-5551 [Electronic] England
• PMID: 27479180 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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