Protein kinase CKIIα interacts with the Bcr moiety of Bcr/Abl and mediates proliferation of Bcr/Abl-expressing cells

Mishra, Suparna; Reichert, Anja; Cunnick, Joan E.; Senadheera, Dinithi; Hemmeryckx, Bianca; Heisterkamp, Nora; Groffen, John

doi:10.1038/sj.onc.1207156

Cited by 46 publications

(40 citation statements)

References 42 publications

(41 reference statements)

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“…8,9,15,25). Some of these inhibitors such as 4,5,6,7-tetrabromobenzimidazole (TBI) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) inhibited the growth of malignant lymphoblastic leukemia cells with a better efficiency than Imatinib (17,18). Pharmacological downregulation of CK2 activity with specific inhibitors induced cell death in drug resistant R-CEM cells (19,20), human colon cancer cell lines and a breast cancer cell line (21).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells

Kaminska¹

2009

Int J Oncol

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Abstract. Malignant gliomas are highly resistant to current therapeutic approaches due to genetic alterations rendering them resistant to cell death. CK2, a ubiquitous and constitutively active serine/threonine kinase, frequently elevated in tumors, contributes to enhanced cell proliferation and resistance to apoptosis. Inhibition of CK2 expression or treatment with inhibitors of CK2 affected survival or induced apoptosis in various cancer cells. Here we compared cytotoxic effects of well-known and new CK2 inhibitors: 4,5,6,7-tetrabromo-1H-benzotriazole (TBB), 4,5,6,7-tetrabromo-1H-benzimidazole (TBI), 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), the related 3-(4,5,6,7-tetrabromo-1H-benzimidazol-1-yl)propan-1-ol (MB001), 3-(4,5,6,7-tetrabromo-1H-1,2,3-benzotriazol-1-yl) propan-1-ol (MB002), 3-(4,5,6,7-tetrabromo-2H-1,2,3-benzotriazol-2-yl)propan-1-ol (MB003) and also structurally similar to above compounds pentabromobenzylisothiourea (ZKK1) and its derivatives (ZKK2-8) on cultured malignant glioma cells. TBI, ZKK1 and MB001-3 were more effective than TBB in inducing growth arrest and cell death in glioma cells. TBI and ZKK1 strongly induced apoptotic death involving caspase 3 and 7 activation followed by PARP cleavage. DMAT strongly upregulated the expression of cytotoxic ligand and its receptor Fas. Structural modifications of ZKK1 largely affected its efficacy: exchange of Br-to Clor F-substituents on the pentabromophenyl ring and inclusion of the bulky N-phenyl substituent in thiourea fragment of ZKK1 diminished cytotoxic activity, while N-substitution with short alkyl groups or an allyl group had opposite effects. Interestingly, TBI at moderate dose did not affect viability of non-transformed astrocytes, suggesting some specificity toward tumor cells in cytotoxic action. TBI, DMAT and ZKK1-induced apoptosis associated with caspase cascade activation in human malignant glioblastoma cells with mutated PT53 and PTEN genes. The reported data demonstrate that suitably modified polybromobenzene molecules exhibit a significant cytotoxic potential towards malignant glioblastoma cells.

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Section: Discussionmentioning

confidence: 99%

Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells

Kaminska¹

2009

Int J Oncol

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“…CK2 in acute lymphoblastic leukemia Mishra et al 40 demonstrated that CK2a is able to interact with the BCR moiety of the p190 or p210 BCR-ABL fusion oncogenes (namely within a fragment between residues 242 --413), which are involved in ALL and CML. CK2 function was shown to be essential for BCR-ABL-bearing tumor cells.…”

Section: Ck2 In Lymphoid Tumors Mouse Modelsmentioning

confidence: 99%

“…Inhibition of CK2 with chemicals, such as 4,5,6,7 --tetrabromobenzimidazole (TBB) or a newly developed CK2 inhibitor, 2 --dimethylamino-4,5,6,7 --tetrabromo-1H-benzimidazole, caused a marked reduction of the proliferation of BCR-ABL-overexpressing cells, in in vitro as well as in in vivo experiments with p190 BCR-ABL1 transgenic mice. 40,41 These initial reports implicating CK2 in lymphoid precursor tumors were followed by the demonstration that CK2 regulates the PI3K/AKT/ PTEN signaling cascade in T-ALL. Silva et al 42 showed that in primary T-ALL cells CK2 is overexpressed or hyperactivated.…”

Section: Ck2 In Lymphoid Tumors Mouse Modelsmentioning

confidence: 99%

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

et al. 2012

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CK2 is a multitask kinase whose role is essential for a countless number of cellular processes, many of which are critical for blood cell development. A prevailing task for this kinase rests on counteracting programmed cell death triggered by multiple stimuli. CK2 is overexpressed in many solid tumors and in vivo mouse models have proven its tumorigenic potential. Recent data have suggested that CK2 may also have a significant role in the pathogenesis of hematopoietic tumors, such as multiple myeloma, chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia and chronic myeloproliferative neoplasms. CK2 regulates hematopoiesis-associated signaling pathways and seems to reinforce biochemical cascades indispensable for tumor growth, proliferation and resistance to conventional and novel cytotoxic agents. Although its activity is multifold, recent evidence supports the rationale of CK2 inhibition as a therapeutic strategy in solid and hematological tumors and phase-I clinical trials are in progress to test the efficacy of this innovative therapeutic approach. In this review, we will summarize the data supporting CK2 as an oncogenic kinase in blood tumors and we will describe some critical signaling pathways, whose regulation by this protein kinase may be implicated in tumorigenesis. Leukemia (2012Leukemia ( ) 26, 1174Leukemia ( --1179 doi:10.1038/leu.2011; published online 13 January 2012Keywords: hematopoiesis; blood tumors; protein kinase CK2; kinase inhibitors INTRODUCTION Protein kinase CK2 is a highly conserved pleiotropic acidophilic serine-threonine kinase whose essential role in several cellular processes has been increasingly appreciated over the last decade. 1 Structurally, CK2 is a tetrameric enzyme, composed by the assembly of two catalytic (a and/or a') and two regulatory b subunits. The catalytic and regulatory subunits may also be present in the cell as unassembled molecules and it seems that this state is associated with distinct and specific functions. The two catalytic subunits a and a' share 90% sequence homology in their N-terminal region. The regulatory subunit b instead does not have any similarity to the other two subunits. 2 CK2 recognizes motifs characterized by a S/T N-terminal to acidic amino acids, its minimum consensus being S/T-X-X-Ac, where X is any amino acid and Ac is a residue with a carboxylic or phosphorylated side chain (E, D, pS, pY).The spectrum of actions of this kinase is impressive as it can phosphorylate hundreds of substrate proteins, which are involved in disparate cellular processes, such as regulation of cell structure, division, proliferation, programmed death, DNA damage repair, protein translation, gene transcription, organelle function and so forth. 3 It has been estimated that a substantial proportion of the human phosphoproteome (up to 20%) is generated by CK2 alone. For this reason, CK2 has long been viewed as a 'non-targetable' kinase for therapeutic purposes.The essential role of CK2 for cell and organism life is underscored by th...

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“…31 Notably, Casein Kinase II was described as a druggable substrate of BCR-ABL, although its function in CML is still unclear. [32][33][34][35] Importantly, it was clearly demonstrated that BCR-ABL/CKII complex plays an essential role in the regulation of imatinib resistance. 36 To verify whether PTEN tail phosphorylation is regulated by BCR-ABL, the BCR-ABL inhibitor imatinib and/or the casein kinase inhibitor TBB were utilized in BCR-ABL expressing NIH3T3 cells and PTEN phosphorylation levels were assessed by western immunoblot, upon normalization of PTEN levels.…”

Section: Cd34mentioning

confidence: 99%

BCR-ABL inactivates cytosolic PTEN through Casein Kinase II mediated tail phosphorylation

Morotti¹,

Panuzzo²,

Crivellaro³

et al. 2015

Cell Cycle

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The tumor suppressive function of PTEN is exerted within 2 different cellular compartments. In the cytosolmembrane, it negatively regulates PI3K-AKT pathway through the de-phosphorylation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), therefore blocking one of the major signaling transduction pathways in tumorigenesis. In the nucleus, PTEN controls genomic stability and cellular proliferation through phosphatase independent mechanisms. Importantly, impairments in PTEN cellular compartmentalization, changes in protein levels and post-transductional modifications affect PTEN tumor suppressive functions. Targeting mechanisms that inactivate PTEN promotes apoptosis induction of cancer cells, without affecting normal cells, with appealing therapeutic implications. Recently, we have shown that BCR-ABL promotes PTEN nuclear exclusion by favoring HAUSP mediated PTEN de-ubiquitination in Chronic Myeloid Leukemia. Here, we show that nuclear exclusion of PTEN is associated with PTEN inactivation in the cytoplasm of CML cells. In particular, BCR-ABL promotes Casein Kinase II-mediated PTEN tail phosphorylation with consequent inhibition of the phosphatase activity toward PIP3. Targeting Casein Kinase II promotes PTEN reactivation with apoptosis induction. We therefore propose a novel BCR-ABL/CKII/PTEN pathway as a potential target to achieve synthetic lethality with tyrosine kinase inhibitors.

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Protein kinase CKIIα interacts with the Bcr moiety of Bcr/Abl and mediates proliferation of Bcr/Abl-expressing cells

Cited by 46 publications

References 42 publications

Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells

Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

BCR-ABL inactivates cytosolic PTEN through Casein Kinase II mediated tail phosphorylation

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