Abstract
Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of α catalytic and β regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed. Moreover, the novel, clinical-grade, ATP-competitive CK2-inhibitor CX-4945 (Silmitasertib) was assayed on lymphoma cells. CK2 was detected in 98.4% of cases with a trend towards a stronger CK2α immunostain in BL compared to FL and DLBCL. No significant differences were observed between Germinal Center B (GCB) and non-GCB DLBCL types. GEP data and WB confirmed elevated CK2 mRNA and protein levels as well as active phosphorylation of specific targets in NHL cells. CX-4945 caused a dose-dependent growth-arresting effect on GCB, non-GCB DLBCL and BL cell-lines and it efficiently shut off phosphorylation of NF-κB RelA and CDC37 on CK2 target sites. Thus, CK2 is highly expressed and could represent a suitable therapeutic target in BL, FL and DLBCL NHL.
Highlights
Protein kinase CK2 is a tetrameric enzyme, composed by two catalytic (α and/or α’) and two regulatory (β) subunits
To fill a gap about to what extent is CK2 expressed in non-Hodgkin lymphomas (NHL) and as to whether its inhibition could affect lymphoma cell viability, the present study evaluated CK2 mRNA and protein levels in the commonest forms of B-cell NHL: Follicular Lymphoma (FL), Diffuse Large B-Cell Lymphoma (DLBCL) and Burkitt Lymphoma (BL)
Our results clearly demonstrate that CK2 is widely expressed in the vast majority of the commonest subtypes of NHL
Summary
Protein kinase CK2 is a tetrameric enzyme, composed by two catalytic (α and/or α’) and two regulatory (β) subunits. CK2 and its orthologs are highly conserved throughout evolution and are involved in the phosphorylation of hundreds of protein targets (20% of human phosphoproteome) [1]. The wide spectrum of possible phosphorylation substrates justifies the pleiotropic roles of CK2 in cell biology. In vitro studies have demonstrated that CK2 is involved in cell cycle regulation, gene expression, protein translation, DNA repair and programmed cell-death [2]. The over-expression of such kinase has been documented in prostate, breast, lung, head and neck and colon carcinomas [7,8,9,10,11,12,13]
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