D11-­Mediated Inhibition of Protein Kinase CK2 Impairs HIF-­1α-­Mediated Signaling in Human Glioblastoma Cells

Susanne Schaefer, Tina Holm Svenstrup, Mette Fischer, Barbara Guerra

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Abstract

Compelling evidence indicates that protein kinase CK2 plays an important role in many steps of cancer initiation and progression, therefore, the development of effective and cell-permeable inhibitors targeting this kinase has become an important objective for the treatment of a variety of cancer types including glioblastoma. We have recently identified 1,3-dichloro-6-[(E)-((4- methoxyphenyl)imino)methyl]dibenzo(b,d)furan-2,7-diol (D11) as a potent and selective inhibitor of protein kinase CK2. In this study, we have further characterized this compound and demonstrated that it suppresses CK2 kinase activity by mixed type inhibition (K I 7.7 nM, K Iʹ 42 nM). Incubation of glioblastoma cells with D11 induces cell death and upon hypoxia the compound leads to HIF-1α destabilization. The analysis of differential mRNA expression related to human hypoxia signaling pathway revealed that D11-mediated inhibition of CK2 caused strong down-regulation of genes associated with the hypoxia response including ANGPTL4, CA9, IGFBP3, MMP9, SLC2A1 and VEGFA. Taken together, the results reported here support the notion that including D11 in future treatment regimens might turn out to be a promising strategy to target tumor hypoxia to overcome resistance to radio- and chemotherapy.

Original languageEnglish
Article number5
JournalPharmaceuticals
Volume10
Issue number1
Number of pages14
ISSN1424-8247
DOIs
Publication statusPublished - 2017

Keywords

  • CK2
  • D11
  • Gene expression profiling
  • Glioblastoma cells
  • HIF-1α

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