Discovery of a Therapeutic Agent for Glioblastoma Using a Systems Biology-Based Drug Repositioning Approach
<p>Overview of study design and methodology. (<b>A</b>) Data from three different GBM cohorts were included in the study. (<b>B</b>) Representation of computational systems biology approaches used in the analysis was visualized. Cox survival analysis was used to identify the prognostic genes whose expression levels indicated the GBM patients’ survival outcomes. Weighted gene co-expression network analysis (WGCNA) was performed to identify the key gene modules related to patients’ prognoses and to investigate the centrality of genes in these modules. DEG analysis was performed to identify the genes associated with the survival analysis and WGCNA. (<b>C</b>) The sequence from the prognostic gene pool to the drug repositioning process is illustrated. Prognostic genes were narrowed to discover the candidate target genes suitable for drug repositioning. Drug repositioning was performed to identify promising drug candidates for modulating the target genes and their neighbouring genes in the gene clusters. (<b>D</b>) In vitro validation was performed to test the effect of the drug candidate.</p> "> Figure 2
<p>Integrative systems biology approaches for the identification of prognostic gene markers. (<b>A</b>) The red circle represents the intersection between the Cox-survival prognostic analysis. The number of unfavourable genes (<b>A.1</b>), favourable genes (<b>A.2</b>), and upregulated prognostic genes (<b>A.3</b>) are shown in three different datasets. (<b>B</b>) The hypergeometric test was performed to compare each dataset’s Cox and DEG results. (<b>C</b>) The figure shows the comparison of UPGs and modules derived from WGCNA using the hypergeometric test. (<b>D</b>) The figure represents the significantly overlapped modules with the UPGs (<b>D.1</b>) and the number of intersection genes between selected modules (<b>D.2</b>). In the module name, T, C1, and C2 affix represent TCGA, CGGA_325, and CGGA_693, respectively. * Hypergeometric test: <span class="html-italic">p</span>-value ≤ 0.05.</p> "> Figure 3
<p>Functional enrichment analysis unveiling significant biological process and pathway alterations. (<b>A</b>) Significantly altered Gene Ontology (GO) biological processes (<b>A.1</b>) and KEGG pathways (<b>A.2</b>) for UPGs are shown. (<b>B</b>) Significantly altered GO biological processes (<b>B.1</b>) and KEGG pathway (<b>B.2</b>) for URPGs are shown. (<b>C</b>) Significantly altered GO biological process (<b>C.1</b>) and KEGG pathways (<b>C.2</b>) for FPGs are shown. Count: This represents the number of genes from the relevant gene pool that are included in the corresponding term. For each category, the cut-off value for significantly altered terms was set at p.adjust ≤ 0.05 obtained with Benjamini–Hochberg adjustment.</p> "> Figure 4
<p>Expression and cell survival profile of <span class="html-italic">CHST2</span>. Cox-survival results and gene expression (Transcript Per Million (TPM) value) profile of <span class="html-italic">CHST2</span> comparing health conditions are presented. (<b>A.1</b>–<b>A.3</b>): <span class="html-italic">CHST2</span> gene expression levels and Cox survival analysis results from the TCGA, CGGA_693, and CGGA_325 cohorts, respectively. <span class="html-italic">p</span>: <span class="html-italic">p</span>-value.</p> "> Figure 5
<p>Overview of drug repositioning strategy. Drug repositioning strategy used in this study.</p> "> Figure 6
<p>Efficacy of candidate drugs on GBM cell line: in vitro validation. The effect of WZ-4002 and Carbinoxamine treatment on the cell viability/migration as well as the target protein <span class="html-italic">CHST2</span> is presented. (<b>A</b>) The expression levels of target protein (<span class="html-italic">CHST2</span>) after treatment of WZ-4002 and Carbinoxamine in U-138 MG cells for two days are presented. The effect of WZ-4002 (10 µM) on <span class="html-italic">EGFR</span> expression is shown. β-actin was used as a loading control. (<b>B</b>) The evaluation of the U-138 MG cell viability after two days of the WZ-4002 and Carbinoxamine treatments is presented. (<b>C</b>) Images from wound healing experiments at different time points. Scale bar = 100 μm. Cell viability and wound healing rates are presented as means ± SD from triplicate measurement and * <span class="html-italic">p</span> ≤ 0.05, ** <span class="html-italic">p</span> ≤ 0.01, *** <span class="html-italic">p</span> ≤ 0.001.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Survival Analysis Identifies Prognostic Genes for GBM
2.2. DEG Analysis Supports Survival Results
2.3. WGCNA Identify Mostly Connected Genes in GBM
2.4. Discovery of Target Genes for Effective Treatment of GBM
2.5. Drug Repositioning for Treatment of the GBM
2.6. In Vitro Validation of Drug Candidate
3. Discussion
4. Materials and Method
4.1. Data Acquisition and Pre-Processing
4.2. Survival Analysis
4.3. DEG Analysis
4.4. Co-Expression Network Analysis
4.5. Functional Enrichment Analysis
4.6. Drug Target Identification
4.7. Drug Repositioning
4.8. Cell Culture and Drug Treatment
4.9. Western Blot Analysis
4.10. Cell Viability Assay
4.11. Wound Healing Assay
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Genes | Short Information |
---|---|
ARRDC4 * | Arrestin domain containing 4 is involved in the regulation of cell growth and survival. |
CHST2 * | Carbohydrate sulfotransferase 2 is involved in the synthesis of sulfated proteoglycans and plays a role in the extracellular matrix. |
CHST6 * | Carbohydrate sulfotransferase 6 is involved in the synthesis of sulfated proteoglycans and plays a role in the extracellular matrix. |
CLU * | Clusterin is involved in the extracellular matrix and it is important for cell adhesion and migration. |
DIRAS3 * | DIRAS family GTPase 3 is involved in the regulation of cell growth and survival. |
EN1 * | Engrailed homeobox 1 is involved in the development of the nervous system and plays a role in axon guidance. |
GLIS3 * | GLIS family zinc finger 3 is involved in the regulation of gene expression and plays a role in the development of the kidney. |
GNA12 * | G protein subunit alpha 12 is involved in the regulation of cell growth and survival. |
IBSP * | Integrin-binding sialoprotein is involved in the extracellular matrix and is important for cell adhesion and migration. |
LCTL * | Lactase-like, the function of which is to hydrolyse glycosidic bonds and involved in sensory transduction. |
LZTS1 * | Leucine zipper, putative tumour suppressor 1, is involved in the regulation of cell growth and survival. |
MT1F * | Metallothionein 1F is involved in the regulation of metal ions and plays a role in the response to oxidative stress. |
SCARA3 * | Scavenger receptor class A member 3 is involved in the recognition and clearance of damaged cells and plays a role in the immune system. |
DRAXIN ** | Dorsal inhibitory axon guidance protein is involved in the development of the nervous system and plays a role in axon guidance. |
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Kaynar, A.; Ozcan, M.; Li, X.; Turkez, H.; Zhang, C.; Uhlén, M.; Shoaie, S.; Mardinoglu, A. Discovery of a Therapeutic Agent for Glioblastoma Using a Systems Biology-Based Drug Repositioning Approach. Int. J. Mol. Sci. 2024, 25, 7868. https://doi.org/10.3390/ijms25147868
Kaynar A, Ozcan M, Li X, Turkez H, Zhang C, Uhlén M, Shoaie S, Mardinoglu A. Discovery of a Therapeutic Agent for Glioblastoma Using a Systems Biology-Based Drug Repositioning Approach. International Journal of Molecular Sciences. 2024; 25(14):7868. https://doi.org/10.3390/ijms25147868
Chicago/Turabian StyleKaynar, Ali, Mehmet Ozcan, Xiangyu Li, Hasan Turkez, Cheng Zhang, Mathias Uhlén, Saeed Shoaie, and Adil Mardinoglu. 2024. "Discovery of a Therapeutic Agent for Glioblastoma Using a Systems Biology-Based Drug Repositioning Approach" International Journal of Molecular Sciences 25, no. 14: 7868. https://doi.org/10.3390/ijms25147868
APA StyleKaynar, A., Ozcan, M., Li, X., Turkez, H., Zhang, C., Uhlén, M., Shoaie, S., & Mardinoglu, A. (2024). Discovery of a Therapeutic Agent for Glioblastoma Using a Systems Biology-Based Drug Repositioning Approach. International Journal of Molecular Sciences, 25(14), 7868. https://doi.org/10.3390/ijms25147868