Cell division cycle 7-kinase inhibitor PHA-767491 hydrochloride suppresses glioblastoma growth and invasiveness

Abstract

BackgroundGenomic instability is a hallmark of cancer cells, and this cellular phenomenon can emerge as a result of replicative stress. It is possible to take advantage of replicative stress, and enhance it in a targeted way to fight cancer cells. One of such strategies involves targeting the cell division cycle 7-related protein kinase (CDC7), a protein with key roles in regulation of initiation of DNA replication. CDC7 overexpression is present in different cancers, and small molecule inhibitors of the CDC7 have well-documented anti-tumor effects. Here, we aimed to test the potential of CDC7 inhibition as a new strategy for glioblastoma treatment.MethodsPHA-767491 hydrochloride was used as the CDC7 inhibitor. Two glioblastoma cell lines (U87-MG and U251-MG) and a control cell line (3T3) were used to characterize the effects of CDC7 inhibition. The effect of CDC7 inhibition on cell viability, cell proliferation, apoptosis, migration, and invasion were analyzed. In addition, real-time PCR arrays were used to identify the differentially expressed genes in response to CDC7 inhibition.ResultsOur results showed that CDC7 inhibition reduces glioblastoma cell viability, suppresses cell proliferation, and triggers apoptosis in glioblastoma cell lines. In addition, we determined that CDC7 inhibition also suppresses glioblastoma cell migration and invasion. To identify molecular targets of CDC7 inhibition, we used real-time PCR arrays, which showed dysregulation of several mRNAs and miRNAs.ConclusionsTaken together, our findings suggest that CDC7 inhibition is a promising strategy for treatment of glioblastoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0364-8) contains supplementary material, which is available to authorized users.

Targeted treatment for glioblastoma: Revisiting conventional strategies and novel targets

“…PHA-767491 hidroklorür, ilk nesil CDC7 inhibitörlerinden biri olup, PHA-767491 hidroklorür uygulamasının >60 kanser hücre hattı üzerinde sitotoksik etki gösterdiği rapor edilmiştir (58) . Glioblastoma hücre hatları üzerinde yaptığımız bir çalışmada, PHA-767491 hidroklorür uygulamasının glioblastoma hücre çoğalmasını engellediğini, apoptotik hücre ölümünü tetiklediğini, hücrelerin migrasyon ve invazyon özelliklerini baskıladı-ğını ortaya koyduk (61) . Glioblastomada görülen nüks vakalarının, tümörün invazif özellikleriyle (migrasyon ve invazyon) yakın ilişkili olduğu göz önüne alındığında, elde ettiğimiz sonuçlar CDC7 aktivitesinin baskılanmasının glioblastoma tedavisi için umut verici bir strateji olduğuna işaret etmektedir.…”

CDC7-dependent transcriptional regulation of RAD54L is essential for tumorigenicity and radio-resistance of glioblastoma

“…Cell division cycle 7-related protein kinase(CDC7) has been identified as an enzyme that is essential for DNA replication and the overexpression of CDC7 and its downstream targets has been reported in multiple types of human cancers including ovarian cancer, melanoma, colorectal cancer, pancreatic cancer and glioblastoma [16] , [17] , [18] , [19] . Bonte [16] et al reported that CDC7-Dbf4 kinase overexpression could be correlated with p53 inactivation then promotes tumor growth through regulation of cell cycles.…”

“…Therefore, alterations in CDC7/DBF4 protein activity during tumorigenesis may have important consequences for tumor cell survival, underlining the potential of CDC7 as an anticancer target [17] , [21] . Erbayraktar et al [19] reported that CDC7 inhibition reduces glioblastoma cell viability, suppresses cell proliferation, and triggers apoptosis in glioblastoma cell lines. However, the downstream target and the functional role of CDC7 in GBM still need further investigation.…”

High‐throughput Docking and Molecular Dynamics Simulations towards the Identification of Novel Peptidomimetic Inhibitors against CDC7

“…The cell division cycle 7 (CDC7) is an evolutionary conserved kinase that activates and regulates DNA replication origins throughout S phase of the cell cycle . Subunits of the heterohexameric minichromosome maintenance (MCM) complex, DNA replicative helicase, are characterized targets for phosphorylation by CDC7 .…”

“…[4] The cell division cycle 7 (CDC7) is an evolutionary conserved kinase that activates and regulates DNA replication origins throughout S phase of the cell cycle. [5] Subunits of the heterohexameric minichromosome maintenance (MCM) complex, DNA replicative helicase, are characterized targets for phosphorylation by CDC7. [6] CDC7 kinase activity is controlled by a regulatory subunit called DBF4, which is expressed during S-phase and regulate CDC7 activity during the cell cycle.…”