Targeting Protein Kinase CK2 Suppresses Prosurvival Signaling Pathways and Growth of Glioblastoma

Abstract

Purpose Gliomas are the most frequently occurring primary malignancies in the brain, and glioblastoma (GBM) is the most aggressive of these tumors. Protein kinase CK2 is composed of two catalytic subunits (α and/or α’) and two β regulatory subunits. CK2 suppresses apoptosis, promotes neo-angiogenesis, and enhances activation of the JAK/STAT, NF-κB, PI3K/AKT, Hsp90, Wnt and Hedgehog pathways. Aberrant activation of the NF-κB, PI3K/AKT and JAK/STAT-3 pathways is implicated in GBM progression. Since CK2 is involved in their activation, the expression and function of CK2 in GBM was evaluated. Experimental Design and Results Analysis of 537 GBMs from The Cancer Genome Atlas Project demonstrates the CSNK2A1 gene, encoding CK2α, has gene dosage gains in GBM (33.7%), and is significantly associated with the classical GBM subtype. Inhibition of CK2 activity by CX-4945, a selective CK2 inhibitor, or CK2 knockdown by siRNA suppresses activation of the JAK/STAT, NF-κB and AKT pathways and downstream gene expression in human GBM xenografts. On a functional level, CX-4945 treatment decreases the adhesion and migration of GBM cells, in part through inhibition of integrin β1 and α4 expression. In vivo, CX-4945 inhibits activation of STAT-3, NF-κB p65 and AKT, and promotes survival of mice with intracranial human GBM xenografts. Conclusions CK2 inhibitors may be considered for treatment of patients with GBM.

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

“…On the contrary, both TGF-β1 and TNF-α, which are overexpressed in GBMs, did increase the activity of CK2α in malignant glioma cultures (Fig. 3), suggesting that the constitutive hyperactivity in malignant gliomas is not solely due to defined genetic changes, contrary to what was previously suggested (9).…”

“…As a result, clinical trials are being designed to treat these tumors with small CK2 drug inhibitors (9). In order for such trials to be adequately designed however, one must define whether all GBMs are likely to benefit from this treatment, or if predictive markers of efficacy can be defined.…”

“…CK2 has been reported to regulate tumor-initiating cell growth, tumor cell survival, DNA repair following ionizing radiation, and apoptosis in these tumors (4,5,7,8,(11)(12)(13). As a result, CK2 inhibition with drug inhibitors or siRNA technology was shown to alter the growth, survival and migration of glioma cell lines and slow down the growth of GBMs xenografts in immunodeficient mice (9,14).…”

“…CK2 is frequently overexpressed or overactive in aggressive forms of solid and hematological malignancies (2,3), and contributes to the dysregulation of cell growth, invasion, survival and senescence via the β-catenin, JAK/STAT, mTOR, and NF-κB pathways (4)(5)(6)(7)(8)(9). As a result, CK2 inhibitors have recently entered preliminary clinical trials for advanced solid and hematological tumors (source: ClinicalTrial.gov, accessed in December 2015).…”

“…CK2 has been reported to regulate tumor-initiating cell growth, tumor cell survival, DNA repair following ionizing radiation, and apoptosis in these tumors (4,5,7,8,(11)(12)(13). As a result, CK2 inhibition with drug inhibitors or siRNA technology was shown to alter the growth, survival and migration of glioma cell lines and slow down the growth of GBMs xenografts in immunodeficient mice (9,14).Prior to translating these findings to the bedside however, it remains unclear whether CK2 hyperactivity is restricted to classical GBMs presenting a CSNK2A1 amplification or not and/or whether all malignant glial tumors are evenly likely to benefit from CK2 inhibitory strategies.This report provides evidence that CK2 kinase hyperactivity occurs in vivo in all classes of GBMs as well as in glial tumors of lower grades and histology, and can be a target independently of Verhaak's classes and its TP53 status. However, additional factors, such as the NF-κB response to CK2 inhibition, may modulate the efficacy of this therapeutic strategy.…”