Therapeutic targeting of CK2 in acute and chronic leukemias

Buontempo, Francesca; McCubrey, James A.; Orsini, Ester; Ruzzene, Maria; Cappellini, Alessandra; Lonetti, Annalisa; Evangelisti, Camilla; Chiarini, Francesca; Barata, João T.; Martelli, Alberto M.

doi:10.1038/leu.2017.301

Cited by 76 publications

(81 citation statements)

References 101 publications

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“…CSK2 in particular is a key regulator of several signaling networks and is overexpressed in many hematological cancers. 74 The activity of CDK2 (and potentially also CDK4, CDK6, CDK7 and CDK9) in RELAPSE patients may further increase AML cell proliferation by triggering G1-S-phase transitions. 75 Several phosphoproteins were multi-phosphorylated, like BCL11A with several phosphosites upregulated in the RELAPSE group (S205, T208, S608, S625, S630 and S718).…”

Section: Comprehensive Ksea Sequence Logos and Antibody Blotting Anamentioning

confidence: 99%

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Aasebø

Berven

Bartaula-Brevik

et al. 2019

Preprint

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word count: 213 Number of figures and tables: 5 Number of references: 84 Key Points  V-ATPases and RNA processing proteins are downregulated and upregulated, respectively, in relapse patients  Relapse patients show higher activity of CSK2 and CDKs when compared to relapse-free patients AbstractAcute myeloid leukemia (AML) is a hematological cancer that mainly affects the elderly.Although complete remission (CR) is achieved for majority of the patients after induction and consolidation therapies, nearly two-thirds relapse within a short interval. Understanding biological factors that determine relapse has therefore become of major clinical interest in AML.We utilized liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify protein changes and protein phosphorylation events associated with AML relapse in primary cells from 41 AML patients at time of diagnosis. Patients were defined as relapse-free if they had not relapsed within a 5-year clinical follow-up after AML diagnosis. Relapse was associated with increased expression of RNA processing proteins and decreased expression of V-ATPase proteins. We also observed an increase in phosphorylation events catalyzed by cyclin-dependent kinases (CDKs) and casein kinase 2 (CSK2). The biological relevance of the proteome findings was supported by cell proliferation assays using inhibitors of V-ATPase (bafilomycin), CSK2 (CX-4945), CDK4/6 (abemaciclib) and CDK2/7/9 (SNS-032). While bafilomycin preferentially inhibited the cells from relapse patients, the kinase inhibitors were less efficient in these cells.This suggests that therapy against the upregulated kinases also could target the factors inducing their upregulation rather than their activity. In conclusion, our study presents markers that could help predict AML relapse and direct therapeutic strategies.

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Section: Comprehensive Ksea Sequence Logos and Antibody Blotting Anamentioning

confidence: 99%

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Aasebø

Berven

Bartaula-Brevik

et al. 2019

Preprint

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“…Although, OGR1 has been reported as novel metastasis suppressor gene, the molecular mechanism is yet to be understood. In this study, we demonstrate to show that OGR1 regulates expression of a cellular enzyme which acts as a regulator of several hallmarks of cancer cell behaviour CK2α [16][17][18] and an important membrane enzyme, neutral endopeptidase 24.11 (NEP, neprilysin, enkephalinase, CD 10). Our finding is the first report, to the best of our knowledge, to demonstrate that the expression of CSNK2A3 (CK2αP) is regulated by a G protein coupled receptor, OGR1.…”

Section: Discussionmentioning

confidence: 79%

“…Casein kinase 2α (CK2α) acts as a regulator of several hallmarks of cancer cell behaviour [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Ovarian cancer G protein-coupled receptor 1 inhibits A549 cells Migration through Casein kinase 2α intronless gene

Sharma

Meitei

Singh

et al. 2019

Preprint

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We have previously reported that ovarian cancer G protein-coupled receptor 1 (OGR1) is a new metastasis suppressor gene. We have also reported for the first time that a new intronless gene for casein kinase 2α (CSNK2A3) is expressed in human cells. The promoter of the well-known casein kinase 2α (CSNK2A1) displays characteristics of housekeeping gene whereas CSNK2A3 has a characteristic of a regulated promoter with two TATA boxes and a CAAT box. In this study, we found that OGR1 upregulates expression of CSNK2A3 by about 3 folds in A549 cells but not CSNK2A1. OGR1 also upregulates expression of neutral endopeptidase (NEP). The OGR1 induced inhibition of A549 cell migration is completely abrogated by inhibition of casein kinase 2α activity, whereas partial abrogation (~ 30%) was observed in the presence of NEP inhibition. The results also revealed that OGR1 regulates CSNK2A3 via activation of Rac1/cdc42 and MAPKs pathways. CK2 is ubiquitously expressed and in contrast it is believed to be a constitutively active enzyme and its regulation appears to be independent of known second messengers. There is no previous report on how expression of CK2α in cancer cells is regulated although many studies have report of aberrant expression of the kinase in cancer. In the current study, we are reporting for the first time the regulation of intronless casein kinase 2α gene, CSNK2A3 in cancer cells. Our findings suggest that the aberrantly casein kinase 2α expression found in various cancer cells may the due to CSNK2A3 expression which is potentially regulated by several master regulators of the developmental pathways rather than well-known casein kinase 2α gene, CSNK2A1.

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“…The pleiotropic CK2 kinase, involved in multiple cellular processes such as proliferation, apoptosis, and cell cycle, is an attractive target for design and development of new antitumor agents 1–3 . CK2 could be responsible for cellular and biochemical mechanisms of cancer formation 4 as well as antitumor drug resistance development 5 .…”

Section: Introductionmentioning

confidence: 99%

The halogenation of natural flavonoids, baicalein and chrysin, enhances their affinity to human protein kinase CK2

et al. 2020

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A series of halogenated derivatives of natural flavonoids: baicalein and chrysin were designed and investigated as possible ligands for the catalytic subunit of tumor-associated human kinase CK2. Thermal shift assay method, in silico modeling, and high-performance liquid chromatography-derived hydrophobicity together with IC 50 values determined in biochemical assay were used to explain the ligand affinity to the catalytic subunit of human protein kinase CK2. Obtained results revealed that substitution of baicalein and chrysin with halogen atom increases their binding affinity to hCK2α, and for 8-chlorochrysin the observed effect is even stronger than for the reference CK2 inhibitor-4,5,6,7-tetrabromo-1H-benzotriazole. The cytotoxic activities of the baicalein and chrysin derivatives in the in vitro model have been evaluated for MV4-11 (human biphenotypic B myelomonocytic leukemia), A549 (human lung adenocarcinoma), LoVo (human colon cancer), and MCF-7 (human breast cancer) as well as on the nontumorigenic human breast epithelial MCF-10A cell lines. Among the baicalein derivatives, the strongest cytotoxic effect was observed for 8-bromobaicalein, which exhibited the highest activity against breast cancer cell line MCF-7 (IC 50 10 ± 3 μM). In the chrysin series, the strongest cytotoxic effect was observed for unsubstituted chrysin, which exhibited the highest activity against leukemic cell line MV4-11 (IC 50 10 ± 4 μM). K E Y W O R D Sbaicalein, chromatographic hydrophobicity index, chrysin, CK2 kinase inhibition, cytotoxic effect, flavonoids, thermal shift assay Abbreviations: BSA, bovine serum albumin; DFT, discrete Fourier transform; DMSO, dimethyl sulfoxide; DSF, differential scanning fluorimetry; gHSQC, gradient heteronuclear single quantum correlation; hCK2α, catalytic subunit of human protein kinase CK2; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide;

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Therapeutic targeting of CK2 in acute and chronic leukemias

Cited by 76 publications

References 101 publications

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Ovarian cancer G protein-coupled receptor 1 inhibits A549 cells Migration through Casein kinase 2α intronless gene

The halogenation of natural flavonoids, baicalein and chrysin, enhances their affinity to human protein kinase CK2

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