Phosphoproteomic Landscape of AML Cells Treated with the ATP-Competitive CK2 Inhibitor CX-4945
Open Access
- 5 February 2021
- Vol. 10 (2), 338
- https://doi.org/10.3390/cells10020338
Abstract
Casein kinase 2 (CK2) regulates a plethora of proteins with pivotal roles in solid and hematological neoplasia. Particularly, in acute myeloid leukemia (AML) CK2 has been pointed as an attractive therapeutic target and prognostic marker. Here, we explored the impact of CK2 inhibition over the phosphoproteome of two cell lines representing major AML subtypes. Quantitative phosphoproteomic analysis was conducted to evaluate changes in phosphorylation levels after incubation with the ATP-competitive CK2 inhibitor CX-4945. Functional enrichment, network analysis, and database mining were performed to identify biological processes, signaling pathways, and CK2 substrates that are responsive to CX-4945. A total of 273 and 1310 phosphopeptides were found differentially modulated in HL-60 and OCI-AML3 cells, respectively. Despite regulated phosphopeptides belong to proteins involved in multiple biological processes and signaling pathways, most of these perturbations can be explain by direct CK2 inhibition rather than off-target effects. Furthermore, CK2 substrates regulated by CX-4945 are mainly related to mRNA processing, translation, DNA repair, and cell cycle. Overall, we evidenced that CK2 inhibitor CX-4945 impinge on mediators of signaling pathways and biological processes essential for primary AML cells survival and chemosensitivity, reinforcing the rationale behind the pharmacologic blockade of protein kinase CK2 for AML targeted therapy.Funding Information
- Bundesministerium für Bildung und Forschung (01DN18015)
This publication has 91 references indexed in Scilit:
- Phosphorylation events during viral infections provide potential therapeutic targetsReviews in Medical Virology, 2011
- Site-specific Phosphorylation Dynamics of the Nuclear Proteome during the DNA Damage ResponseMolecular & Cellular Proteomics, 2010
- DYRK1A and DYRK3 Promote Cell Survival through Phosphorylation and Activation of SIRT1Online Journal of Public Health Informatics, 2010
- Nuclear functions of the HMG proteinsBiochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2010
- Global Effects of Kinase Inhibitors on Signaling Networks Revealed by Quantitative PhosphoproteomicsMolecular & Cellular Proteomics, 2009
- KEA: kinase enrichment analysisBioinformatics, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- Structure-based design of small peptide inhibitors of protein kinase CK2 subunit interactionBiochemical Journal, 2007
- DYRK1A Autophosphorylation on Serine Residue 520 Modulates Its Kinase Activity via 14-3-3 BindingMolecular Biology of the Cell, 2007
- Protein kinase CK2 phosphorylates and upregulates Akt/PKBCell Death & Differentiation, 2005