Abstract
BackgroundThe 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.MethodsWe 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.ResultsCK2α 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.ConclusionsThese 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.
Highlights
The involvement of protein kinase CK2 in sustaining cancer cell survival could have implications in the resistance to conventional and unconventional therapies
We show that CK2 controls Acute myeloid leukemia (AML) cell survival, modulates AML cell sensitivity to daunorubicin and impinge on the p53 and STAT3 survival regulating signaling pathways
We analyzed CK2 expression in AML cell lines and AML cells from patients classified according to the European LeukemiaNet (ELN) classification, which distinguishes different prognostic groups according to cytogenetic alterations and mutations to specific genes [23]
Summary
The involvement of protein kinase CK2 in sustaining cancer cell survival could have implications in the resistance to conventional and unconventional therapies. AML encompasses an array of biologically distinct diseases that differ with regard to the pathogenesis, clinical course, response to therapy and prognosis [1]. Malignant clones that are endowed with the capability of escaping spontaneous and drug-induced programmed cell death are selected during the course of the disease. AML - initially responsive to chemotherapy in a large proportion of cases becomes subsequently refractory to drug-induced apoptosis. A critical research goal is the identification of the molecular mechanisms accounting for uncontrolled AML cell growth and resistance to apoptosis in order to design novel, molecularly based, targeted therapies [2,3]
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