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Functional drug-target-disease network analysis of gene-phenotype connectivity for curcumin in hepatocellular
Yuanyuan Zhao1, Jiahao Tao2, Zhuangzhong Chen2
1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China.
Background:
The anti-tumor properties of curcumin have been demonstrated for many types of cancer. However, a systematic functional and biological analysis of its target proteins has yet to be fully documented. The aim of this study was to explore the underlying mechanisms of curcumin and broaden the perspective of targeted therapies.
Methods:
Direct protein targets (DPTs) of curcumin were searched in the DrugBank database. Using the STRING database, the interactions between curcumin and DPTs and indirect protein targets (IPTs) weres documented. The protein-protein interaction (PPI) network of curcumin-mediated proteins was visualized using Cytoscape. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed for all curcumin-mediated proteins. Furthermore, the cancer targets were searched in the Comparative Toxicogenomics Database (CTD). The overlapping targets were studied using Kaplan-Meier analysis to evaluate cancer survival. Further genomic analysis of overlapping genes was conducted using the cBioPortal database. Lastly, MTT, quantitative polymerase chain reaction (qPCR), and western blot (WB) analysis were used to validate the predicted results on hepatocellular carcinoma (HCC) cells.
Results:
A total of five DPTs and 199 IPTs were found. These protein targets were found in 121 molecular pathways analyzed via KEGG enrichment. Based on the anti-tumor properties of curcumin, two pathways were selected, including pathways in cancer (36 genes) and HCC (22 genes). Overlapping with 505 HCC-related gene sets identified in CTD, five genes (TP53, RB1, TGFB1, GSTP1, and GSTM1) were finally identified. High mRNA levels of TP53, RB1, and GSTM1 indicated a prolonged overall survival (OS) in HCC, whereas elevated mRNA levels of TGFB1 were correlated with poor prognosis. The viability of both HepG2 cells and Hep3B cells was significantly reduced by curcumin at concentrations of 20 or 30 μM after 48 or 72 h of culture. At a concentration of 20 μM curcumin cultured for 48 h, the expression of TGFB1 and GSTP1 in Hep3B cells was reduced significantly in qPCR analysis, and reduced TGFB1 protein expression was also found in Hep3B cells.
Insights
Curcumin exhibits anti-tumor effects by targeting specific proteins involved in cancer pathways. This study identified key genes like TP53 and TGFB1, validating curcumin
Area of Science:
- Molecular Biology
- Bioinformatics
- Cancer Research
Background:
- Curcumin demonstrates anti-tumor properties across various cancers.
- A comprehensive analysis of curcumin's protein targets and mechanisms is needed.
- Understanding these targets can inform novel therapeutic strategies.
Purpose of the Study:
- To systematically identify and analyze the protein targets of curcumin.
- To elucidate the molecular mechanisms underlying curcumin's anti-cancer effects.
- To explore curcumin as a potential targeted therapy for cancer, particularly hepatocellular carcinoma (HCC).
Main Methods:
- Curcumin's direct and indirect protein targets were identified using DrugBank and STRING databases.
- Protein-protein interaction networks were constructed and analyzed with Cytoscape.
- Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed.
- Comparative Toxicogenomics Database (CTD) was used to identify overlapping cancer targets.
- Kaplan-Meier analysis and cBioPortal were employed for survival and genomic analysis.
- Experimental validation was conducted using MTT, qPCR, and Western blot on HCC cells.
Main Results:
- Five direct and 199 indirect protein targets of curcumin were identified.
- Curcumin-mediated proteins were enriched in 121 molecular pathways, including cancer and HCC pathways.
- Five key overlapping genes (TP53, RB1, TGFB1, GSTP1, GSTM1) were identified.
- High TP53, RB1, and GSTM1 mRNA levels correlated with better HCC survival, while high TGFB1 mRNA indicated poor prognosis.
- Curcumin reduced HCC cell viability and modulated the expression of TGFB1 and GSTP1.
Conclusions:
- Curcumin targets key proteins involved in cancer and HCC pathways.
- TP53, RB1, TGFB1, GSTP1, and GSTM1 are significant in curcumin's anti-tumor activity and HCC prognosis.
- Curcumin demonstrates therapeutic potential for HCC by affecting cell viability and specific gene expression.
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