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In Silico Analysis Reveals MDM2 as a Potential Target of Ursolic Acid for Overcoming Tamoxifen Resistance in Breast
Yohanes Surya Jati1,2, Diyah Novi Sekarini1,2, Nur Ayunie Zulkepli3,4
1Department of Biotechnology, The Graduate School, Universitas Gadjah Mada, Yogyakarta, Indonesia.
Objective:
Ursolic acid (UA) has been proven to inhibit various cancer signaling pathways; however, the involvement of UA in overcoming tamoxifen resistance remains unclear and needs further investigation. This study aims to discover the potential gene targets and explore how ursolic acid interacts with those genes to restore sensitivity to tamoxifen.
Methods:
Analyzing gene expression data from GeneCards and Swisstargetprediction for UA related genes, and the Gene Expression Omnibus (GEO) for tamoxifen resistance genes. DEGs were analyzed for functional annotation and molecular pathways using DAVID v6.8, continued with constructing a protein-protein interaction (PPI) network to highlight crucial genes associated with tamoxifen resistance using STRING-DB and Cytoscape. Genetic alteration analysis using cBioportal for target validation and consideration. Molecular docking was done using Autodock4 and PyMoL for visualisation.
Results:
The KEGG pathway and PPI network suggest that MDM2, STAT3, TGFB1, and MAPK1 were indicated as potential target genes of UA. Genetic alteration analysis further confirms that MDM2 has the highest alteration, which becomes potentially targeted by UA. Molecular docking analysis confirms that UA can target MDM2 by targeting the N-terminus site on 4HBM and 5ZXF structure. The binding energy of UA is -5.36 for 4HBM and -8.71 for 5ZXF, with all RMSD values below 2. This result shows that UA has a lower docking score than the native ligand for the 5ZXF structure. Additionally, MDM2 is mainly involved in the PI3K-Akt pathway, which plays a role in the chemotherapy resistance mechanism.
Conclusion:
MDM2 has become a potential target for UA to reverse the tamoxifen resistance mechanism in breast cancer.
Insights
Ursolic acid may overcome tamoxifen resistance in breast cancer by targeting the MDM2 gene. This study identified MDM2 as a key player in tamoxifen resistance, suggesting a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tamoxifen resistance is a major challenge in breast cancer treatment.
- Ursolic acid (UA) exhibits anti-cancer properties by inhibiting various signaling pathways.
- The role of UA in overcoming tamoxifen resistance requires further investigation.
Purpose of the Study:
- To identify potential gene targets of ursolic acid (UA) in overcoming tamoxifen resistance.
- To explore the interaction mechanisms between UA and its target genes.
- To investigate UA's potential to restore tamoxifen sensitivity in breast cancer.
Main Methods:
- Gene expression analysis using GeneCards, Swisstargetprediction, and GEO datasets.
- Functional annotation and pathway analysis (DAVID v6.8).
- Protein-protein interaction (PPI) network construction (STRING-DB, Cytoscape).
- Genetic alteration analysis (cBioportal).
- Molecular docking simulations (Autodock4, PyMoL).
Main Results:
- MDM2, STAT3, TGFB1, and MAPK1 were identified as potential UA targets.
- MDM2 showed the highest genetic alteration and was confirmed as a target for UA via molecular docking.
- UA demonstrated favorable binding energy with MDM2 structures (4HBM and 5ZXF).
- MDM2 is implicated in the PI3K-Akt pathway, a known mechanism in chemotherapy resistance.
Conclusions:
- MDM2 is a potential therapeutic target for ursolic acid (UA) to reverse tamoxifen resistance in breast cancer.
- UA's interaction with MDM2 may restore sensitivity to tamoxifen treatment.
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