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 (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.
Highlights
Glioblastoma is the most common primary tumor of the central nervous system and one of the most lethal types of human cancer
Since the high incidence of phosphatase and tensin homolog (PTEN) mutation observed in glioblastoma cells has been strongly associated with stimulation of HIF-1α-mediated gene expression and increased apoptotic resistance [6], we investigated whether D11-mediated cell death induction was accompanied by destabilization and/or inhibition of HIF-1α transcription factor and, if so, how does D11 influence the expression of genes regulated by HIF-1α under hypoxic conditions
D11 was identified employing the catalytic α-subunit of protein kinase CK2 following a screening of a small-molecule compound library of the Diversity Set III under the drug discovery and therapeutic program (DTP) of the National Cancer Institute (NCI, Rockville, MD, USA, [11])
Summary
Glioblastoma is the most common primary tumor of the central nervous system and one of the most lethal types of human cancer. A comprehensive characterization of over 200 samples from patients diagnosed with glioblastoma has provided a detailed map of the many genomic and transcriptional alterations that occur in this type of malignancy and that contribute to its aggressive character [3,4,5]. Cancer genomic studies have revealed that multiple components of the aforementioned pathway are frequently targeted by germline or somatic mutations contributing to tumor resistance to both radiotherapy and chemotherapy [5]. In this respect, glioblastoma has one of the highest incidence rates of phosphatase and tensin homolog (PTEN) mutation that has been strongly associated with a selective advantage for tumor expansion [6]. Loss of PTEN expression results in hyperactivation of the pro-survival PI3K/AKT pathway and increased resistance to apoptosis [7]
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