Targeting protein kinase CK2 suppresses prosurvival signaling pathways and growth of glioblastoma

Ying Zheng, Braden C. McFarland, Denis Drygin, Hao Yu, Susan L. Bellis, Hyunsoo Kim, Markus Bredel, Etty N. Benveniste

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

Abstract

Purpose: Gliomas are the most frequently occurring primary malignancies in the brain, and glioblastoma 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 neoangiogenesis, and enhances activation of the JAK/STAT, NF-κB, PI3K/AKT, Hsp90, Wnt, and Hedgehog pathways. Aberrant activation of the NF-κB, PI3Kappa;/AKT, and JAK/STAT-3 pathways is implicated in glioblastoma progression. As CK2 is involved in their activation, the expression and function of CK2 in glioblastoma was evaluated. Experimental Design and Results: Analysis of 537 glioblastomas from The Cancer Genome Atlas Project demonstrates the CSNK2A1 gene, encoding CK2α, has gene dosage gains in glioblastoma (33.7%), and is significantly associated with the classical glioblastoma 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 glioblastoma xenografts. On a functional level, CX-4945 treatment decreases the adhesion and migration of glioblastoma 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 glioblastoma xenografts. CK2 inhibitors may be considered for treatment of patients with glioblastoma.

Original languageEnglish (US)
Pages (from-to)6484-6494
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number23
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

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