Protein kinase CK2 inhibition is associated with the destabilization of HIF-1α in human cancer cells

Barbara Guerra; Tine D L Rasmussen; Alexander Schnitzler; Hans H Jensen; Brigitte S Boldyreff; Yoshihiko Miyata; Niels Marcussen; Karsten Niefind; Olaf-Georg Issinger

doi:10.1016/j.canlet.2014.10.026

Protein kinase CK2 inhibition is associated with the destabilization of HIF-1α in human cancer cells

Cancer Lett. 2015 Jan 28;356(2 Pt B):751-61. doi: 10.1016/j.canlet.2014.10.026. Epub 2014 Oct 28.

Authors

Barbara Guerra¹, Tine D L Rasmussen¹, Alexander Schnitzler², Hans H Jensen¹, Brigitte S Boldyreff³, Yoshihiko Miyata⁴, Niels Marcussen⁵, Karsten Niefind², Olaf-Georg Issinger⁶

Affiliations

¹ Biomedical Research Group, BMB, University of Southern Denmark, Odense, Denmark.
² Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.
³ KinaseDetect Aps, Odense, Denmark.
⁴ Department of Cell & Developmental Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
⁵ Institute of Pathology, OUH, Odense, Denmark.
⁶ Biomedical Research Group, BMB, University of Southern Denmark, Odense, Denmark; KinaseDetect Aps, Odense, Denmark. Electronic address: [email protected].

PMID: 25449433
DOI: 10.1016/j.canlet.2014.10.026

Abstract

Screening for protein kinase CK2 inhibitors of the structural diversity compound library (DTP NCI/NIH) led to the discovery of 4-[(E)-(fluoren-9-ylidenehydrazinylidene)-methyl]benzoic acid (E9). E9 induces apoptotic cell death in various cancer cell lines and upon hypoxia, the compound suppresses CK2-catalyzed HSP90/Cdc37 phosphorylation and induces HIF-1α degradation. Furthermore, E9 exerts a strong anti-tumour activity by inducing necrosis in murine xenograft models underlining its potential to be used for cancer treatment in future clinical studies. Crystal structure analysis of human and maize CK2α in complex with E9 reveals unique binding properties of the inhibitor to the enzyme, accounting for its affinity and selectivity.

Keywords: HIF-1α; Kinase inhibitors; Murine xenograft; Protein kinase CK2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzoates / pharmacology*
Blotting, Western
Casein Kinase II / antagonists & inhibitors*
Cell Cycle / drug effects
Cell Proliferation / drug effects*
Combinatorial Chemistry Techniques
Female
Fluorenes / pharmacology*
Fluorescent Antibody Technique
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / chemistry*
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Immunoenzyme Techniques
Luciferases / metabolism
Mice
Mice, Nude
Neoplasms / drug therapy*
Neoplasms / enzymology
Neoplasms / pathology
Phosphorylation / drug effects
Protein Conformation / drug effects*
Protein Kinase Inhibitors / pharmacology*
Signal Transduction / drug effects*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

4-((fluoren-9-ylidenehydrazinylidene)methyl)benzoic acid
Benzoates
Fluorenes
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Protein Kinase Inhibitors
Luciferases
Casein Kinase II