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

Leukemia ◽  
2016 ◽  
Vol 31 (2) ◽  
pp. 292-300 ◽  
Author(s):  
L Quotti Tubi ◽  
S Canovas Nunes ◽  
A Brancalion ◽  
E Doriguzzi Breatta ◽  
S Manni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Protein Kinase ◽  
Cell Viability ◽  
Myeloid Leukemia ◽  
Protein Kinase Ck2 ◽  
Kinase Ck2 ◽  
Acute Myeloid

Protein Kinase CK2 Is Associated with Poor Clinical Outcome and Regulates the Expression of Anti-Apoptotic Proteins and PTEN Phosphorylation in Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2356-2356
Author(s):  
June-Won Cheong ◽  
Ju In Eom ◽  
Jin Koo Lee ◽  
Sun Young Park ◽  
Yuri Kim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Catalytic Activity ◽  
Protein Kinase ◽  
Myeloid Leukemia ◽  
Protein Kinase Ck2 ◽  
Normal Karyotype ◽  
Poor Clinical Outcome ◽  
Pten Protein ◽  
Kinase Ck2 ◽  
Acute Myeloid

Abstract We previously demonstrated that the phosphorylation of c-terminal regulatory domain of phosphatase and tensin homologue (PTEN) protein are frequently observed and significantly associated with poor clinical outcome in acute myeloid leukemia (AML). Phosphorylation of PTEN stabilizes the PTEN protein, but makes it less active towards its substrate, phosphatidylinositol 3,4,5-triphosphate, resulting in an antagonizing the apoptotic pathways. Protein kinase CK2 is implicated in many cellular processes including the cell proliferation, survival, and tumorigenesis. However, the biological significance of CK2 expression and its association with PTEN phosphorylation has not been evaluated. In this study, we evaluated the protein kinase CK2 activity/expression and PTEN phosphorylation simultaneously in leukemic blasts obtained from 59 patients with AML with normal karyotype. Western blot analysis revealed that PTEN phosphorylation was observed in 30 (50.9%) cases. CK2 expression was significantly associated with CK2 catalytic activity and PTEN phosphorylation. Levels of CK2 catalytic activity were significantly higher in AML cases with PTEN phosphorylation (p-PTEN-positive) compared with those without PTEN phosphorylation (p-PTEN-negative) (P<0.05). Age, sex, white blood cell count, and complete remission rate were not different according to the CK2 expression. However, the overall survival was significantly shorter in AML cases with high CK2 expression (P< 0.05). Treatment of p-PTEN-positive AML cells with apigenin, a specific inhibitor of CK2, abolished the phosphorylation of PTEN, as well as Ser473 phosphorylation of Akt/PKB, in a dose-dependent manner. CK2 overexpression induced an increase in the proportion of cells in the G(2)/M phase. Induced overexpression of CK2 in U937 leukemia cells led to PTEN phosphorylation, Ser473 Akt/PKB phosphorylation, in addition to an increased expression of Bcl-2, Bcl-xL, Mcl-1, Survivin, and XIAP proteins. Taken together, these results suggest that the phosphorylation of PTEN and expression of anti-apoptotic proteins were directly regulated by protein kinase CK2 in AML cells. We also demonstrate, for the first time, that CK2 is an independent prognostic variable in AML patients with normal karyotype. These findings additionally extend our understanding of the role of CK2 in AML, and suggest the CK2 molecule as a potential target for AML treatment.

scholarly journals Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300

2021 ◽  
Author(s):  
Mauro Rosales ◽  
George V. Perez ◽  
Ailyn C. Ramon ◽  
Yiliam Cruz ◽  
Arielis Rodriguez-Ulloa ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Kinase ◽  
Myeloid Leukemia ◽  
Ribosomal Proteins ◽  
Protein Kinase Ck2 ◽  
Clinical Grade ◽  
Kinase Ck2 ◽  
Major Target ◽  
Acute Myeloid

Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based CK2 inhibitor CIGB-300 on AML cells proliferation and viability. CIGB-300 internalization and subcellular distribution were also studied, and the role of B23/nucleophosmin 1 (NPM1), a major target for the peptide in solid tumors, was addressed by knock-down in model cell lines. Finally, pull-down experiments and phosphoproteomic analysis were performed to study CIGB-interacting proteins and identify the array of CK2 substrates differentially modulated after treatment with the peptide. Importantly, CIGB-300 elicited a potent anti-proliferative and proapoptotic effect in AML cells, with more than 80% of peptide transduced cells within three minutes. Unlike solid tumor cells, NPM1 did not appear to be a major target for CIGB-300 in AML cells. However, in vivo pull-down experiments and phosphoproteomic analysis evidenced that CIGB-300 targeted the CK2α catalytic subunit, different ribosomal proteins, and inhibited the phosphorylation of a common CK2 substrates array among both AML backgrounds. Remarkably, our results not only provide cellular and molecular insights unveiling the complexity of the CIGB-300 anti-leukemic effect in AML cells, but also reinforce the rationale behind the pharmacologic blockade of protein kinase CK2 for AML targeted therapy.

scholarly journals Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 766
Author(s):  
Mauro Rosales ◽  
George V. Pérez ◽  
Ailyn C. Ramón ◽  
Yiliam Cruz ◽  
Arielis Rodríguez-Ulloa ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Kinase ◽  
Myeloid Leukemia ◽  
Ribosomal Proteins ◽  
Protein Kinase Ck2 ◽  
Clinical Grade ◽  
Kinase Ck2 ◽  
Major Target ◽  
Acute Myeloid

Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), an advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based CK2 inhibitor CIGB-300 on AML cells proliferation and viability. CIGB-300 internalization and subcellular distribution were also studied, and the role of B23/nucleophosmin 1 (NPM1), a major target for the peptide in solid tumors, was addressed by knock-down in model cell lines. Finally, pull-down experiments and phosphoproteomic analysis were performed to study CIGB-interacting proteins and identify the array of CK2 substrates differentially modulated after treatment with the peptide. Importantly, CIGB-300 elicited a potent anti-proliferative and proapoptotic effect in AML cells, with more than 80% of peptide transduced cells within three minutes. Unlike solid tumor cells, NPM1 did not appear to be a major target for CIGB-300 in AML cells. However, in vivo pull-down experiments and phosphoproteomic analysis evidenced that CIGB-300 targeted the CK2α catalytic subunit, different ribosomal proteins, and inhibited the phosphorylation of a common CK2 substrates array among both AML backgrounds. Remarkably, our results not only provide cellular and molecular insights unveiling the complexity of the CIGB-300 anti-leukemic effect in AML cells but also reinforce the rationale behind the pharmacologic blockade of protein kinase CK2 for AML-targeted therapy.

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