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Cancer Cell International
Published in: Cancer Cell International 1/2016

Open Access 01-12-2016 | Primary research

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

Authors: Zubeyde Erbayraktar, Begum Alural, Resat Serhat Erbayraktar, Erdogan Pekcan Erkan

Published in: Cancer Cell International | Issue 1/2016

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Abstract

Background

Genomic 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.

Methods

PHA-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.

Results

Our 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.

Conclusions

Taken together, our findings suggest that CDC7 inhibition is a promising strategy for treatment of glioblastoma.
Appendix
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Literature
1.
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.CrossRefPubMedPubMedCentral
2.
Dobbelstein M, Sorensen CS. Exploiting replicative stress to treat cancer. Nat Rev Drug Discovery. 2015;14(6):405–23.CrossRefPubMed
3.
Lei M, Kawasaki Y, Young MR, Kihara M, Sugino A, Tye BK. Mcm2 is a target of regulation by Cdc7-Dbf4 during the initiation of DNA synthesis. Genes Dev. 1997;11(24):3365–74.CrossRefPubMedPubMedCentral
4.
5.
Chuang LC, Teixeira LK, Wohlschlegel JA, Henze M, Yates JR, Mendez J, Reed SI. Phosphorylation of Mcm2 by Cdc7 promotes pre-replication complex assembly during cell-cycle re-entry. Mol Cell. 2009;35(2):206–16.CrossRefPubMedPubMedCentral
6.
Bonte D, Lindvall C, Liu H, Dykema K, Furge K, Weinreich M. Cdc7-Dbf4 kinase overexpression in multiple cancers and tumor cell lines is correlated with p53 inactivation. Neoplasia. 2008;10(9):920–31.CrossRefPubMedPubMedCentral
7.
Choschzick M, Lebeau A, Marx AH, Tharun L, Terracciano L, Heilenkotter U, Jaenicke F, Bokemeyer C, Simon R, Sauter G, et al. Overexpression of cell division cycle 7 homolog is associated with gene amplification frequency in breast cancer. Hum Pathol. 2010;41(3):358–65.CrossRefPubMed
8.
Cheng AN, Jiang SS, Fan CC, Lo YK, Kuo CY, Chen CH, Liu YL, Lee CC, Chen WS, Huang TS, et al. Increased Cdc7 expression is a marker of oral squamous cell carcinoma and overexpression of Cdc7 contributes to the resistance to DNA-damaging agents. Cancer Lett. 2013;337(2):218–25.CrossRefPubMed
9.
Nambiar S, Mirmohammadsadegh A, Hassan M, Mota R, Marini A, Alaoui A, Tannapfel A, Hegemann JH, Hengge UR. Identification and functional characterization of ASK/Dbf4, a novel cell survival gene in cutaneous melanoma with prognostic relevance. Carcinogenesis. 2007;28(12):2501–10.CrossRefPubMed
10.
Melling N, Muth J, Simon R, Bokemeyer C, Terracciano L, Sauter G, Izbicki JR, Marx AH. Cdc7 overexpression is an independent prognostic marker and a potential therapeutic target in colorectal cancer. Diagn Pathol. 2015;10:125.CrossRefPubMedPubMedCentral
11.
Montagnoli A, Moll J, Colotta F. Targeting cell division cycle 7 kinase: a new approach for cancer therapy. Clin Cancer Res. 2010;16(18):4503–8.CrossRefPubMed
12.
Montagnoli A, Valsasina B, Croci V, Menichincheri M, Rainoldi S, Marchesi V, Tibolla M, Tenca P, Brotherton D, Albanese C, et al. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nat Chem Biol. 2008;4(6):357–65.CrossRefPubMed
13.
Sasi NK, Tiwari K, Soon FF, Bonte D, Wang T, Melcher K, Xu HE, Weinreich M. The potent Cdc7-Dbf4 (DDK) kinase inhibitor XL413 has limited activity in many cancer cell lines and discovery of potential new DDK inhibitor scaffolds. PLoS ONE. 2014;9(11):e113300.CrossRefPubMedPubMedCentral
14.
Koltun ES, Tsuhako AL, Brown DS, Aay N, Arcalas A, Chan V, Du H, Engst S, Ferguson K, Franzini M, et al. Discovery of XL413, a potent and selective CDC7 inhibitor. Bioorg Med Chem Lett. 2012;22(11):3727–31.CrossRefPubMed
15.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2[-Delta Delta C(T)] Method. Methods. 2001;25(4):402–8.CrossRefPubMed
16.
Alural B, Duran GA, Tufekci KU, Allmer J, Onkal Z, Tunali D, Genc K, Genc S. EPO mediates neurotrophic, neuroprotective, anti-oxidant, and anti-apoptotic effects via downregulation of miR-451 and miR-885-5p in SH-SY5Y neuron-like cells. Front Immunol. 2014;5:475.CrossRefPubMedPubMedCentral
17.
Rodriguez-Acebes S, Proctor I, Loddo M, Wollenschlaeger A, Rashid M, Falzon M, Prevost AT, Sainsbury R, Stoeber K, Williams GH. Targeting DNA replication before it starts: Cdc7 as a therapeutic target in p53-mutant breast cancers. Am J Pathol. 2010;177(4):2034–45.CrossRefPubMedPubMedCentral
18.
Huggett MT, Tudzarova S, Proctor I, Loddo M, Keane MG, Stoeber K, Williams GH, Pereira SP. Cdc7 is a potent anti-cancer target in pancreatic cancer due to abrogation of the DNA origin activation checkpoint. Oncotarget. 2016.
19.
Chen JR, Yao Y, Xu HZ, Qin ZY. Isocitrate dehydrogenase (IDH)1/2 mutations as prognostic markers in patients with glioblastomas. Medicine (Baltimore). 2016;95(9):e2583.CrossRef
20.
Ichimura K, Pearson DM, Kocialkowski S, Backlund LM, Chan R, Jones DT, Collins VP. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro-Oncology. 2009;11(4):341–7.CrossRefPubMedPubMedCentral
21.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003.CrossRefPubMed
22.
Caldera V, Mellai M, Annovazzi L, Monzeglio O, Piazzi A, Schiffer D. MGMT hypermethylation and MDR system in glioblastoma cancer stem cells. Cancer Genom Proteom. 2012;9(4):171–8.
23.
Qiu ZK, Shen D, Chen YS, Yang QY, Guo CC, Feng BH, Chen ZP. Enhanced MGMT expression contributes to temozolomide resistance in glioma stem-like cells. Chin J Cancer. 2014;33(2):115–22.CrossRefPubMedPubMedCentral
24.
Godlewski J, Bronisz A, Nowicki MO, Chiocca EA, Lawler S. microRNA-451: a conditional switch controlling glioma cell proliferation and migration. Cell Cycle. 2010;9(14):2742–8.CrossRefPubMed
25.
Godlewski J, Nowicki MO, Bronisz A, Nuovo G, Palatini J, De Lay M, Van Brocklyn J, Ostrowski MC, Chiocca EA, Lawler SE. MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. Mol Cell. 2010;37(5):620–32.CrossRefPubMedPubMedCentral
26.
Drusco A, Bottoni A, Lagana A, Acunzo M, Fassan M, Cascione L, Antenucci A, Kumchala P, Vicentini C, Gardiman MP, et al. A differentially expressed set of microRNAs in cerebro-spinal fluid (CSF) can diagnose CNS malignancies. Oncotarget. 2015;6(25):20829–39.CrossRefPubMedPubMedCentral
27.
Flannery T, Gibson D, Mirakhur M, McQuaid S, Greenan C, Trimble A, Walker B, McCormick D, Johnston PG. The clinical significance of cathepsin S expression in human astrocytomas. Am J Pathol. 2003;163(1):175–82.CrossRefPubMedPubMedCentral
28.
Flannery T, McQuaid S, McGoohan C, McConnell RS, McGregor G, Mirakhur M, Hamilton P, Diamond J, Cran G, Walker B, et al. Cathepsin S expression: an independent prognostic factor in glioblastoma tumours–A pilot study. Int J Cancer J Int Du Cancer. 2006;119(4):854–60.CrossRef
29.
Zhang L, Wang H, Xu J, Zhu J, Ding K. Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways. Toxicol Lett. 2014;228(3):248–59.CrossRefPubMed
30.
Kenig S, Alonso MB, Mueller MM, Lah TT. Glioblastoma and endothelial cells cross-talk, mediated by SDF-1, enhances tumour invasion and endothelial proliferation by increasing expression of cathepsins B, S, and MMP-9. Cancer Lett. 2010;289(1):53–61.CrossRefPubMed
31.
Sevenich L, Bowman RL, Mason SD, Quail DF, Rapaport F, Elie BT, Brogi E, Brastianos PK, Hahn WC, Holsinger LJ, et al. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat Cell Biol. 2014;16(9):876–88.CrossRefPubMedPubMedCentral
Metadata
Title
Cell division cycle 7-kinase inhibitor PHA-767491 hydrochloride suppresses glioblastoma growth and invasiveness
Authors
Zubeyde Erbayraktar
Begum Alural
Resat Serhat Erbayraktar
Erdogan Pekcan Erkan
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2016
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-016-0364-8

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