Protein kinase CK2 is important for the function of glioblastoma brain tumor initiating cells

Abstract

Protein kinase CK2 is a ubiquitously expressed serine/threonine kinase composed of two catalytic subunits (α) and/or (α′) and two regulatory (β) subunits. The expression and kinase activity of CK2 is elevated in many different cancers, including glioblastoma (GBM). Brain tumor initiating cells (BTICs) are a subset of cells that are highly tumorigenic and promote the resistance of GBM to current therapies. We previously reported that CK2 activity promotes prosurvival signaling in GBM. In this study, the role of CK2 signaling in BTIC function was examined. We found that expression of CK2α was increased in CD133+ BTICs compared to CD133- cells within the same GBM xenolines. Treatment with CX-4945, an ATP-competitive inhibitor of CK2, led to reduced expression of Sox2 and Nestin, transcription factors important for the maintenance of stem cells. Similarly, inhibition of CK2 also reduced the frequency of CD133+ BTICs over the course of 7 days, indicating a role for CK2 in BTIC persistence and survival. Importantly, using an in vitro limiting dilution assay, we found that inhibition of CK2 kinase activity with CX-4945 or siRNA knockdown of the CK2 catalytic subunits reduced neurosphere formation in GBM xenolines of different molecular subtypes. Lastly, we found that inhibition of CK2 led to decreased EGFR levels in some xenolines, and combination treatment with CX-4945 and Gefitinib to inhibit CK2 and EGFR, respectively, provided optimal inhibition of viability of cells. Therefore, due to the integration of CK2 in multiple signaling pathways important for BTIC survival, CK2 is a promising target in GBM.

Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy – potential clinical relevance

“…Therefore, CK2 inhibition mediated by CX-4945 leads to inhibition of the MGMT DNA-repairing activity, thereby potentiating the efficacy of temozolomide [55,77]. The relevance of targeting CK2 in GBM, one of the most aggressive brain tumours in adults, has been widely shown [56,78,79], and the efficacy of the CX-4945/temozolomide combination therapy has been proven also in this malignancy. Indeed, combining these two drugs reduced the proliferation of several GBM cell lines and effectively inhibited tumour growth in mouse xenograft models, significantly prolonging their survival compared to the single-drug treated ones [57,58].…”

Simultaneous CK2/TNIK/Dyrk1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease

“…Among the relevant substrates of CK2 that could impact chemotherapy sensitivity are ABC proteins (P-gp/MDR and MRP1) that are pumps responsible for e ux of chemotherapeutic agents 57 , and XRCC1/XRCC4 which regulate DNA single and double-stranded break repair 58 . Inhibition of CK2 kinase activity or expression inhibited growth and induced apoptosis of multiple cancer cell types in vitro 59,60,61,62 and suppressed the stem-like tumor initiating cells in glioblastomas 63,64 .…”

Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2

“…N 5. P 367-378 doi: http://dx.doi.org/10.7124/bc.000960 state is supported by the fact that "Silmitasertib" (СХ-4945) is verified on the second stage of clinical testing and might be a perspective antitumor drug [4,11]. Hence, the research for new protein kinase inhibitors is fairly relevant.…”

“…Protein kinase СК2 (Casein kinase 2), one of significant molecular targets, is the polysubstrate serine/threonine kinase present in all eukaryotic cells. This enzyme is an important link of numerous signal ways of a cell and is involved in various pathological processes [4,5]. This protein kinase is known to have an increased activity in inflammatory tissues and many tumors.…”