Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Nov 16;24(22):16396.
doi: 10.3390/ijms242216396.

Identification of CDK1, PBK, and CHEK1 as an Oncogenic Signature in Glioblastoma: A Bioinformatics Approach to Repurpose Dapagliflozin as a Therapeutic Agent

Harold A Chinyama  1 , Li Wei  2   3   4 , Ntlotlang Mokgautsi  5   6 , Bashir Lawal  7 , Alexander T H Wu  8   9   10 , Hsu-Shan Huang  5   6   11   12
Affiliations

Identification of CDK1, PBK, and CHEK1 as an Oncogenic Signature in Glioblastoma: A Bioinformatics Approach to Repurpose Dapagliflozin as a Therapeutic Agent

Harold A Chinyama et al. Int J Mol Sci. .

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor whose median survival is less than 15 months. The current treatment regimen comprising surgical resectioning, chemotherapy with Temozolomide (TMZ), and adjuvant radiotherapy does not achieve total patient cure. Stem cells' presence and GBM tumor heterogeneity increase their resistance to TMZ, hence the poor overall survival of patients. A dysregulated cell cycle in glioblastoma enhances the rapid progression of GBM by evading senescence or apoptosis through an over-expression of cyclin-dependent kinases and other protein kinases that are the cell cycle's main regulatory proteins. Herein, we identified and validated the biomarker and predictive properties of a chemoradio-resistant oncogenic signature in GBM comprising CDK1, PBK, and CHEK1 through our comprehensive in silico analysis. We found that CDK1/PBK/CHEK1 overexpression drives the cell cycle, subsequently promoting GBM tumor progression. In addition, our Kaplan-Meier survival estimates validated the poor patient survival associated with an overexpression of these genes in GBM. We used in silico molecular docking to analyze and validate our objective to repurpose Dapagliflozin against CDK1/PBK/CHEK1. Our results showed that Dapagliflozin forms putative conventional hydrogen bonds with CDK1, PBK, and CHEK1 and arrests the cell cycle with the lowest energies as Abemaciclib.

Keywords: Abemaciclib; Dapagliflozin; PDZ binding kinase; Temozolomide; cell cycle; checkpoint kinase 1; cyclin-dependent kinase 1; drug repurposing; glioblastoma multiforme; molecular docking.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Differentially expressed genes (DEGs) from GSE108474, GSE50161, and GSE4290 comprise gene expression profiles of GBM. (A–C) Depict the DEGs from GSE108474, GSE50161, and GSE4290 GBM samples with a p-value set at <0.05. The red and blue dots represent up and downregulated genes, respectively. (D) A Venn diagram with 188 overlapping overexpressed genes while (E) comprises 16,625 overlapping-downregulated genes analyzed in BEG. (F) is a list of the 188 overlapping overexpressed genes.
Figure 2
Figure 2
Clustered PPI networks comprising CDK1/PBK/CHEK1 oncogenes in GBM and their functional enrichments. (A) A PPI cluster with a minimum interaction score significance > 0.700, 10 nodes, and 22 edges with an average local clustering coefficient of 0.82 and a PPI enrichment p-value of 2.11 × 10−15. The PPI network is from co-expression, text mining, databases, experiments, co-occurrence, neighborhood, and gene fusion. (B,C) show functional enrichments under the Gene Ontology (GO) biological processes, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathways that were available upon an analysis of the PPI network in the STRING database. (D) A signaling network cluster of KEGG enrichment analysis revealing CDK1/PBK/CHEK1 co-expression in the cell cycle analyzed in Network Analyst.
Figure 3
Figure 3
CDK1/PBK/CHEK1 expression and correlation profiling in GBM. (A–C) CDK1/PBK/CHEK1 is overexpressed in GBM and other cancer types from the TCGA and was analyzed on TIMER2.0. Their mRNA expression levels are expressed as TPM and were normalized and transformed using log transformation with a p-value significance code of 0 ≤ *** < 0.001 ≤ ** < 0.01 ≤ * < 0.05 ≤ . < 0.1. (D–F) represent the positive correlation of CDK1/PBK/CHEK1 in WHO grade IV primary glioma (GBM), with R ranging from 0.702 to 0.813 and a p-value < 0.05 affirming the statistical significance of the association of the CDK1/PBK/CHEK1 oncogenic signature in GBM.
Figure 3
Figure 3
CDK1/PBK/CHEK1 expression and correlation profiling in GBM. (A–C) CDK1/PBK/CHEK1 is overexpressed in GBM and other cancer types from the TCGA and was analyzed on TIMER2.0. Their mRNA expression levels are expressed as TPM and were normalized and transformed using log transformation with a p-value significance code of 0 ≤ *** < 0.001 ≤ ** < 0.01 ≤ * < 0.05 ≤ . < 0.1. (D–F) represent the positive correlation of CDK1/PBK/CHEK1 in WHO grade IV primary glioma (GBM), with R ranging from 0.702 to 0.813 and a p-value < 0.05 affirming the statistical significance of the association of the CDK1/PBK/CHEK1 oncogenic signature in GBM.
Figure 4
Figure 4
CDK1/PBK/CHEK1 overexpression is associated with the late-stage GBM. (A–C) The CDK1/PBK/CHEK1 level overexpression was elevated in the GBM samples normalized and transformed using log2 transformation with a p-value < 0.05 considered statistically significant on the GlioVis tool. (D–F) Boxplots generated from the CGGA analysis reflecting CDK1/PBK/CHEK1 gene overexpression in three WHO glioma grades II, III, and IV with a p-value < 0.05.
Figure 4
Figure 4
CDK1/PBK/CHEK1 overexpression is associated with the late-stage GBM. (A–C) The CDK1/PBK/CHEK1 level overexpression was elevated in the GBM samples normalized and transformed using log2 transformation with a p-value < 0.05 considered statistically significant on the GlioVis tool. (D–F) Boxplots generated from the CGGA analysis reflecting CDK1/PBK/CHEK1 gene overexpression in three WHO glioma grades II, III, and IV with a p-value < 0.05.
Figure 5
Figure 5
CDK1/PBK/CHEK1 overexpression promotes tumor aggressiveness and immunosuppression in GBM. (A–C) depict a moderate positive correlation of CDK1 expression levels with tumor purity (Rho = 0.474) and a strong, moderate, and weak positive correlation with T Cells CD4+ Th2 (Rho = 0.721), MDSCs (Rho = 0.439), and TAM-M2 (Rho = 0.297) infiltration levels in GBM, analyzed on TIMER2.0. (D–F) show a moderate positive correlation of PBK expression level with GBM tumor purity (Rho = 0.459), as well as a strong, moderate, and weak positive correlation with T Cells CD4+ Th2 (Rho = 0.667), MDSCs (Rho = 0.525), and TAM-M2 (Rho = 0.382) infiltration levels. (G–I) show a moderate positive correlation of CHEK1 expression levels with tumor purity (Rho = 0.513), T Cells CD4+ Th2 (Rho = 0.433), and MDSCs (Rho = 0.448), and a weak positive correlation with TAM-M2 (Rho = 0.202) infiltration levels in GBM. CDK1/PBK/CHEK1 mRNA expression levels are expressed as TPM and were normalized and transformed using log2 transformation with a p-value < 0.05.
Figure 6
Figure 6
CDK1/PBK/CHEK1 overexpression in GBM is associated with poor patient survival. (A–C) show a poor prognosis of the highly expressed CDK1, PBK, and CHEK1 oncogenes in GBM with low cut-off values of 1.55, 0.81, and 1.42. KM survival graphs predict a shorter overall survival for the highly expressed oncogenes with a p-value < 0.05. The high expression of the oncogenes is indicated in red with poor overall survival compared to low expressions (in blue) of the same in GBM.
Figure 7
Figure 7
Putative binding interactions of Dapagliflozin with CDK1, PBK, and CHEK1 in 3D and 2D structures. (A,D) Dapagliflozin binding on CDK1 with lower putative binding energy [ΔG = −8.4 kcal/mol] and a short binding distance (GLN132:1.94 Å) stabilized by a H bond in green color. (B,E) represent lower putative binding energy [ΔG = −7.2 kcal/mol] and short binding distance (ASN45:2.81 Å) of Dapagliflozin on PBK. (C,F) confirm that Dapagliflozin has higher binding affinity, evidenced by the lower Gibbs free energy [ΔG = −8.3 kcal/mol] on CHEK1 stabilized by H bond (ASP148:2.37 Å).
Figure 8
Figure 8
Putative binding of Abemaciclib on CDK1 in 3D and 2D structures. (A,B) show a slightly better putative binding of Abemaciclib on CDK1 [ΔG = −8.9 kcal/mol] but has a longer binding distance (LYS33:3.23 Å) stabilized by a H bond in green color compared to Dapagliflozin.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Joel M., Mughal A.A., Grieg Z., Murrell W., Palmero S., Mikkelsen B., Fjerdingstad H.B., Sandberg C.J., Behnan J., Glover J.C., et al. Targeting PBK/TOPK decreases growth and survival of glioma initiating cells in vitro and attenuates tumor growth in vivo. Mol. Cancer. 2015;14:121. doi: 10.1186/s12943-015-0398-x. - DOI - PMC - PubMed
    1. Signore M., Pelacchi F., Di Martino S., Runci D., Biffoni M., Giannetti S., Morgante L., De Majo M., Petricoin E., Stancato L. Combined PDK1 and CHK1 inhibition is required to kill glioblastoma stem-like cells in vitro and in vivo. Cell Death Dis. 2014;5:e1223. doi: 10.1038/cddis.2014.188. - DOI - PMC - PubMed
    1. Ostrom Q.T., Gittleman H., Farah P., Ondracek A., Chen Y., Wolinsky Y., Stroup N.E., Kruchko C., Barnholtz-Sloan J.S. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro-Oncology. 2013;15((Suppl. S2)):ii1–ii56. doi: 10.1093/neuonc/not151. - DOI - PMC - PubMed
    1. Louis D.N., Ohgaki H., Wiestler O.D., Cavenee W.K., Burger P.C., Jouvet A., Scheithauer B.W., Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109. doi: 10.1007/s00401-007-0243-4. - DOI - PMC - PubMed
    1. Ohka F., Natsume A., Wakabayashi T. Current trends in targeted therapies for glioblastoma multiforme. Neurol. Res. Int. 2012;2012:878425. doi: 10.1155/2012/878425. - DOI - PMC - PubMed

MeSH terms