D11-Mediated Inhibition of Protein Kinase CK2 Impairs HIF-1α-Mediated Signaling in Human Glioblastoma Cells
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 typ...
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doaj-da673b75528646928dc0de1054a16f7e2020-11-25T03:55:11ZengMDPI AGPharmaceuticals1424-82472017-01-01101510.3390/ph10010005ph10010005D11-Mediated Inhibition of Protein Kinase CK2 Impairs HIF-1α-Mediated Signaling in Human Glioblastoma CellsSusanne Schaefer0Tina H. Svenstrup1Mette Fischer2Barbara Guerra3Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, DenmarkCompelling 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 (KI 7.7 nM, KI′ 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.http://www.mdpi.com/1424-8247/10/1/5CK2D11HIF-1αglioblastoma cellsgene expression profiling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Susanne Schaefer Tina H. Svenstrup Mette Fischer Barbara Guerra |
spellingShingle |
Susanne Schaefer Tina H. Svenstrup Mette Fischer Barbara Guerra D11-Mediated Inhibition of Protein Kinase CK2 Impairs HIF-1α-Mediated Signaling in Human Glioblastoma Cells Pharmaceuticals CK2 D11 HIF-1α glioblastoma cells gene expression profiling |
author_facet |
Susanne Schaefer Tina H. Svenstrup Mette Fischer Barbara Guerra |
author_sort |
Susanne Schaefer |
title |
D11-Mediated Inhibition of Protein Kinase CK2 Impairs HIF-1α-Mediated Signaling in Human Glioblastoma Cells |
title_short |
D11-Mediated Inhibition of Protein Kinase CK2 Impairs HIF-1α-Mediated Signaling in Human Glioblastoma Cells |
title_full |
D11-Mediated Inhibition of Protein Kinase CK2 Impairs HIF-1α-Mediated Signaling in Human Glioblastoma Cells |
title_fullStr |
D11-Mediated Inhibition of Protein Kinase CK2 Impairs HIF-1α-Mediated Signaling in Human Glioblastoma Cells |
title_full_unstemmed |
D11-Mediated Inhibition of Protein Kinase CK2 Impairs HIF-1α-Mediated Signaling in Human Glioblastoma Cells |
title_sort |
d11-mediated inhibition of protein kinase ck2 impairs hif-1α-mediated signaling in human glioblastoma cells |
publisher |
MDPI AG |
series |
Pharmaceuticals |
issn |
1424-8247 |
publishDate |
2017-01-01 |
description |
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 (KI 7.7 nM, KI′ 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. |
topic |
CK2 D11 HIF-1α glioblastoma cells gene expression profiling |
url |
http://www.mdpi.com/1424-8247/10/1/5 |
work_keys_str_mv |
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