title: Targeting protein kinase CK2 suppresses prosurvival signaling pathways and growth of glioblastoma.
abstract: OBJECTIVE
  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, PI3K/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.
  
  
  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.
  
  
  CONCLUSIONS
  CK2 inhibitors may be considered for treatment of patients with glioblastoma.
authors.affiliation: Authors' Affiliations: Departments of Cell, Developmental and Integrative Biology, Pathology, and Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama; and Cylene Pharmaceuticals, San Diego, California.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.forename: Braden C
authors.initials: BC
authors.lastname: McFarland
authors.forename: Denis
authors.initials: D
authors.lastname: Drygin
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.forename: Susan L
authors.initials: SL
authors.lastname: Bellis
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Kim
authors.forename: Markus
authors.initials: M
authors.lastname: Bredel
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004789:Enzyme Activation; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009287:Naphthyridines / Q000494:pharmacology* / Q000627:therapeutic use; D010619:Phenazines; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009287:Naphthyridines; D010619:Phenazines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C555142:silmitasertib; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt
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