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Abstract
Protein kinase CK2 is a highly pleiotropic and ubiquitously expressed Ser/Thr kinase with instrumental roles in normal and pathological states, including neoplastic phenotype in solid tumor and hematological malignancies. In line with previous reports, CK2 has been suggested as an attractive prognostic marker and molecular target in acute myeloid leukemia (AML), a blood malignant disorder that remains as an unmet medical need. Accordingly, this work investigates the complex landscape of molecular and cellular perturbations supporting the antileukemic effect exerted by CK2 inhibition in AML cells. To identify and functionally characterize the proteomic profile differentially modulated by the CK2 peptide-based inhibitor CIGB-300, we carried out LC-MS/MS and bioinformatic analysis in human cell lines representing two differentiation stages and major AML subtypes. Using this approach, 109 and 129 proteins were identified as significantly modulated in HL-60 and OCI-AML3 cells, respectively. In both proteomic profiles, proteins related to apoptotic cell death, cell cycle progression, and transcriptional/translational processes appeared represented, in agreement with previous results showing the impact of CIGB-300 in AML cell proliferation and viability. Of note, a group of proteins involved in intracellular redox homeostasis was specifically identified in HL-60 cell-regulated proteome, and flow cytometric analysis also confirmed a differential effect of CIGB-300 over reactive oxygen species (ROS) production in AML cells. Thus, oxidative stress might play a relevant role on CIGB-300-induced apoptosis in HL-60 but not in OCI-AML3 cells. Importantly, these findings provide first-hand insights concerning the CIGB-300 antileukemic effect and draw attention to the existence of both common and tailored response patterns triggered by CK2 inhibition in different AML backgrounds, a phenomenon of particular relevance with regard to the pharmacologic blockade of CK2 and personalized medicine.
Highlights
Protein kinases are biological messengers that control multiple processes in cell physiology through reversible phosphorylation of thousands of proteins encoded by the human genome
In HL-60 cells, 25 and 85 proteins were identified as significantly modulated at 30 min and 3 h, while in OCI-AML3 cells, 74 and 58 proteins appeared differentially modulated in response to CIGB-300 treatment (Table 1; Supplementary Table S2)
In the protein kinase landscape that has emerged as attractive targets for cancer treatment, CK2 stands among the most studies in recent years
Summary
Protein kinases are biological messengers that control multiple processes in cell physiology through reversible phosphorylation of thousands of proteins encoded by the human genome. Phosphorylation is a pivotal mechanism for cell homeostasis, and its deregulation may result in aberrant signaling pathways implicated in a variety of human disorders (Cohen, 2002; Ardito et al, 2017). Protein kinase CK2 (formerly known as casein kinase 2) is a ubiquitously expressed and constitutively active enzyme that exists as tetrameric complexes composed by two catalytic (α or α) and two regulatory subunits (β) (Meggio and Pinna, 2003; Venerando et al, 2014). This highly pleiotropic Ser/Thr kinase is responsible for roughly 25% of cellular phosphoproteome, playing instrumental roles in normal and pathological states (Meggio and Pinna, 2003; Borgo et al, 2021). In the past few years, CK2 has emerged as a promising candidate for molecular-targeted therapy in AML, a disease often characterized by poor long-term outcomes and resistance towards standard chemotherapy (Buontempo et al, 2018; Rosales et al, 2021a; Klink et al, 2021)
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