Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential.
Casein kinase II contributes to the growth and survival of malignant gliomas and attracts increasing attention as a therapeutic target in these tumors. Several reports have suggested that this strategy might be most relevant for specific subgroups of patients, namely Verhaak's classical and TP53 wild-type tumors. Using kinase assays and microarray genetic profiling in a series of 27 proprietary fresh frozen surgical glioma samples, we showed that constitutive CK2 kinase activation is not restricted to tumors that present increased copy numbers or mRNA expression of its catalytic or regulatory subunits, and can result from a functional activation by various cytokines from the glioma microenvironment. Using corresponding primary tumor and human astrocyte cell cultures as well as glioma cell lines, we confirmed that CK2 inhibition is selectively toxic to malignant glial tumors, without any restriction to tumor class or to TP53 status. We finally showed that while the contribution of CK2 to the constitutive NF-κB hyperactivation in malignant gliomas is at best moderate, a delayed activation of NF-κB may associate with the therapeutic resistance of glioma cells to CK2 inhibition.
Department of Human Genetics and GIGA Research Center, University of Liège, B-4000 Liège, Belgium.
Nadege
N
Dubois
Department of Human Genetics and GIGA Research Center, University of Liège, B-4000 Liège, Belgium.
Marie
M
Willems
Department of Human Genetics and GIGA Research Center, University of Liège, B-4000 Liège, Belgium.
Minh-Tuan
MT
Nguyen-Khac
Department of Human Genetics and GIGA Research Center, University of Liège, B-4000 Liège, Belgium.
Jerome
J
Kroonen
Department of Human Genetics and GIGA Research Center, University of Liège, B-4000 Liège, Belgium.
Nicolas
N
Goffart
Department of Neuropathology, CHU Liège, University of Liège, B-4000 Liège, Belgium.
Manuel
M
Deprez
Department of Human Genetics and GIGA Research Center, University of Liège, B-4000 Liège, Belgium.
Vincent
V
Bours
Department of Human Genetics and GIGA Research Center, University of Liège, B-4000 Liège, Belgium.
Pierre A
PA
Robe
D047310:Apigenin / Q000494:pharmacology; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004789:Enzyme Activation; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D009287:Naphthyridines / Q000494:pharmacology; D010619:Phenazines; D046888:Tissue Array Analysis / Q000379:methods*; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D009287:Naphthyridines; D010619:Phenazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D047310:Apigenin; C555142:silmitasertib; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II