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.
Protein kinase CK2, cystic fibrosis transmembrane conductance regulator, and the ΔF508 mutation. F508 deletion disrupts a kinase-binding site. VOLUME 282 (2007) PAGES 10804-10813