Protein Kinase CK2 - A Key Suppressor of Apoptosis

Cellular and Molecular Biochemistry Research Laboratory (151), V.A. Medical Center, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55417, USA.
Advances in enzyme regulation 05/2008; 48(1):179-87. DOI: 10.1016/j.advenzreg.2008.04.002
Source: PubMed


Protein kinase CK2 is a ubiquitous and highly conserved protein serine/threonine kinase that is indispensable for cell survival. CK2 has long been implicated in cell growth and proliferation, and studies from several laboratories have suggested that CK2 plays a global role in affecting cell growth related activities. Recently, we documented that CK2, besides its role in cell growth and proliferation, can potently suppress apoptosis. Considering that CK2 has been found to be elevated in all the cancers that have been examined, the ability of CK2 to suppress apoptosis is particularly important in the context of cancer cell pathobiology since these cells exhibit dysregulation of both cell proliferation and cell death. Thus, overexpression of CK2 in cancer cells may impart a survival advantage by its action as a suppressor of apoptotic activity in these cells while promoting cell growth. In experimental studies, we have shown that overexpression of CK2 in cells can potently inhibit apoptosis mediated by a variety of agents including removal of survival factors, chemical and physical agents, and death receptor ligands. On the other hand, inhibition of CK2 by chemical inhibitors or by its molecular downregulation by antisense CK2 ODN or siRNA leads to potent induction of apoptosis. Downregulation of CK2 is associated with apoptosis mediated via effects on several downstream targets, and it appears that CK2 may have a global impact on the apoptotic machinery. While CK2 is present in both the nuclear and cytoplasmic compartments, several of its cell growth and cell death related activities appear to be associated with its signalling to the nuclear structures such as chromatin and nuclear matrix. In general, shuttling of CK2 to these compartments correlates with its role in cell growth and suppression of apoptotic activity whereas loss of CK2 from the nuclear structures is associated with induction of apoptosis and cessation of cell growth. These various observations on the biology of CK2 have led to our original proposal that CK2 is a potentially important target for cancer chemopreventive and therapeutic approaches; this is now being substantiated by recent studies.

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Available from: Khalil Ahmed, Sep 01, 2015
    • "Consequently, CK2 plays a key role in a number of pathways and as a regulator of fundamental cellular processes, ranging from DNA replication and transcription to signalling for cellular growth and damage responses. Presently, its recognized major function is to counteract apoptosis and to promote cell survival (Ahmad et al., 2008; Litchfield, 2003; St-Denis & Litchfield, 2009). CK2 is also involved in several human pathologies, such as neurodegenerative (Perez et al., 2011), vascular, skeletal muscle, and bone tissue diseases, as well as in viral and parasites-borne diseases (Cozza et al., 2010). "
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    ABSTRACT: CK2 is a multifunctional, pleiotropic protein kinase involved in the regulation of cell proliferation and survival. Since fibroblasts from Type 1 Diabetes patients (T1DM) with Nephropathy exhibit increased proliferation, we studied cell viability, basal CK2 expression and activity, and response to specific CK2 inhibitors TBB (4,5,6,7-tetrabenzotriazole) and CX4945, in fibroblasts from T1DM patients either with (T1DM+) or without (T1DM-) Nephropathy, and from healthy controls (N). We tested expression and phosphorylation of CK2-specific molecular targets. In untreated fibroblasts from T1DM+, the cell viability was higher than in both N and T1DM-. CK2 inhibitors significantly reduced cell viability in all groups, but more promptly and with a larger effect in T1DM+. Differences in CK2-dependent phosphorylation sites were detected. In conclusion, our results unveil a higher dependence of T1DM+ cells on CK2 for their survival, despite a similar expression and a lower activity of this kinase compared with those of normal cells.
    Growth factors (Chur, Switzerland) 09/2015; 33(4):1-8. DOI:10.3109/08977194.2015.1073725 · 3.39 Impact Factor
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    • "CK2 plays a key role in proliferation (Guerra and Issinger, 2008; Guerra and Issinger 1999), transformation (Ruzzene and Pinna, 2010), apoptosis (Guerra and Issinger, 2008; Ahmad et al., 2008), survival (Guerra and Issinger, 2008; Ruzzene and Pinna, 2010; Barata, 2011) and cell growth (Meggio and Pinna, 2003; Guerra and Issinger, 2008; Duncan et al., 2010). Beside the involvement CK2 in various cellular functions (Meggio and Pinna, 2003; Ahmad et al., 2008; Canton and Litchfield, 2006), overexpression of CK2 could lead to different number of cancers diseases(Faust et al., 2000; Kramerov et al., 2006; Duncan and Litchfield, 2008; Landesman-Bollag et al., 2001), including breast (Drygin et al., 2011), renal (Landesman- Bollag et al., 2001), leukemias (Piazza et al., 2013), prostate and lung cancers(Guerra and Issinger, 2008). The increased level of CK2 can also result in several central nervous system diseases such as Alzheimer, Parkinson, brain ischemia and memory impairments (Meggio and Pinna 2003; Landesman-Bollag et al., 2001; Sarno and Pinna, 2008). "
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    ABSTRACT: In this work, the quantitative structure-activity relationship models were developed for predicting activity of a series of compounds as CK2 inhibitors using multiple linear regressions and support vector machine methods. The data set consisted of 48 compounds was divided into two subsets of training and test set, randomly. The most relevant molecular descriptors were selected using the genetic algorithm as a feature selection tool. The predictive ability of the models was evaluated using Y- randomization test, cross-validation and external test set. The genetic algorithm- multiple linear regression model with six selected molecular descriptors was obtained and showed high statistical parameters (R2train=0.893, R2test=0.921, Q2LOO= 0.844, F=43.17, RMSE=0.287). Comparison of the results between GA-MLR and GA-SVM demonstrates that GA-SVM provided better results for the training set compounds, however the predictive quality for both models are acceptable. The results suggest that atomic mass and polarizabilities and also number of heteroatom in molecules are the main independent factors contributing to the CK2 inhibition activity. The predicted results of this study can be used to design of new and potent CK2 inhibitors.
    Arabian Journal of Chemistry 01/2015; 9. DOI:10.1016/j.arabjc.2014.12.021 · 3.73 Impact Factor
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    • "Indeed, CK2 has been demonstrated to contribute to the malignant phenotype and tumor progression in mouse models as well as in human cancer cells [8]. To this regard, a peculiar property of CK2 is the ability to protect cells from apoptosis [9]. This action is believed to rely on several mechanisms. "
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    ABSTRACT: Background The 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. Methods We 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. Results CK2α 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. Conclusions These 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.
    Journal of Hematology & Oncology 10/2013; 6(1). DOI:10.1186/1756-8722-6-78 · 4.81 Impact Factor
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