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Unravelling Phyto-Compound Therapeutics Against Colorectal Cancer: Targeting SRC proto-oncogene via Fibroblast Growth
Pankaj Kumar Tripathi1, Chakresh Kumar Jain1
1Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, NOIDA, Uttar Pradesh, 201309, India.
Introduction:
Colorectal cancer is a complex condition influenced by genetic mutations and environmental factors. Due to its intricate nature, the diagnosis and treatment of this condition require a comprehensive approach that considers individual circumstances. The study aimed to identify genes linked with colorectal cancer and their therapeutic agents from natural bioactive compounds.
Methods:
The significantly prognostic differentially expressed genes (DEGs) were screened out from NCBI Gene Expression Omnibus (GEO) datasets. A protein-protein interaction network was constructed using STRING Database, and key genes were identified using Network Analyzer and CytoNCA plugins within Cytoscape. Further analysis involved functional annotations, and biological pathways analysis, SRC mechanism to uncover the role of SRC in CRC. Additionally, we performed virtual screening and molecular docking, Physiochemical property analysis along with MD simulation study to propose suitable natural compounds for promising therapeutic targets.
Results:
The study conducted differential gene expression analysis, identifying 3621 statistically significant genes, with 1467 upregulated and 2154 downregulated. The top ten genes with the highest degree, betweenness centrality, and closeness centrality in the PPI network were selected as key genes. The SRC gene was found to have the highest degree and closeness centrality. Functional annotation and pathway analysis of key genes with a specific focus on the SRC mechanism revealed that the SRC's role in activating the RAS-RAF-MEK-ERK and Wnt/β-catenin pathways in CRC cells, promoting proliferation and invasion. Molecular modelling of SRC led to the screening of phytocompounds from tropical fruits, with Rutin exhibiting a higher docking score compared to FDAapproved anticancer drugs. MD simulations over 100 ns and the post-MD analysis i.e. RMSD, SASA, RMSF, FEL, RG, Hydrogen bond, PCA, and MMPBSA, comprehended the stable and robust interactions of a protein-ligand complex. These findings suggest Rutin's potential as a potent natural molecule for treating CRC.
Conclusion:
The study concludes that SRC plays a pivotal role in CRC, influencing cellular processes critical to cancer development and Rutin has been found to be a promising SRC inhibitor, suggesting a potential alternative therapeutic strategy for CRC. The consistent molecular interactions of Rutin necessitate further validation through wet lab experiments, offering hope for individuals affected by CRC.
Insights
This study identifies SRC as a key gene in colorectal cancer (CRC) development and reveals Rutin, a natural compound, as a potential SRC inhibitor. Further research may validate Rutin as a novel therapeutic agent for CRC.
Area of Science:
- Genomics and Bioinformatics
- Molecular Biology
- Computational Chemistry
Background:
- Colorectal cancer (CRC) is a complex disease driven by genetic mutations and environmental factors, necessitating personalized treatment strategies.
- Identifying key genes and natural therapeutic compounds is crucial for advancing CRC diagnosis and treatment.
Purpose of the Study:
- To identify prognostic genes associated with colorectal cancer (CRC).
- To explore natural bioactive compounds as potential therapeutic agents targeting identified CRC genes.
- To elucidate the role of the SRC gene in CRC progression and its targeted inhibition.
Main Methods:
- Differential gene expression analysis and protein-protein interaction network construction to identify key genes.
- Functional and pathway analysis, focusing on the SRC signaling mechanism in CRC.
- Virtual screening, molecular docking, and molecular dynamics simulations to evaluate natural compounds as SRC inhibitors.
Main Results:
- Identified 3621 significant differentially expressed genes (DEGs) in CRC, with SRC highlighted as a pivotal gene.
- SRC activation of RAS-RAF-MEK-ERK and Wnt/β-catenin pathways promotes CRC cell proliferation and invasion.
- Rutin demonstrated strong binding affinity to SRC, outperforming existing drugs in molecular simulations, suggesting its therapeutic potential.
Conclusions:
- SRC plays a critical role in colorectal cancer (CRC) pathogenesis by influencing key cellular pathways.
- Rutin emerges as a promising natural SRC inhibitor, offering a potential novel therapeutic strategy for CRC.
- Further experimental validation is required to confirm Rutin's efficacy as a CRC treatment.
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