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Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
SRC is a potential target of Arctigenin in treating triple-negative breast cancer: based on machine learning
Yuezhou Huang1, Qing Luo2, Linfeng Li3
1Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China.
Introduction:
This research explores the therapeutic potential of Arctigenin (AG) against triple-negative breast cancer (TNBC) and elucidates its underlying molecular mechanisms.
Methods:
Potential targets of AG and TNBC-related genes were identified through public databases. By intersecting drug-specific and disease-related targets, key genes were selected for further analysis. Differential gene expression profiling and Weighted Gene Co-expression Network Analysis (WGCNA) were performed. Functional enrichment analysis was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Machine learning algorithms were employed to identify hub genes, followed by validation through molecular docking, molecular dynamics (MD) simulations, and surface plasmon resonance (SPR) assays. In vitro experiments including cell viability assays, cell cycle analysis, apoptosis detection, and Western blotting were performed on MDA-MB-453 and MDA-MB-231 cell lines.
Results:
Our study identified 183 AG-related targets, 5,193 differentially expressed genes, and 6,173 co-expression module genes associated with TNBC. Machine learning algorithms pinpointed 4 hub genes from 28 intersecting targets. Molecular docking, Molecular dynamics (MD) and surface plasmon resonance (SPR) indicated a moderately strong interaction between AG and SRC kinase, where the oxygen atom of AG forms hydrogen bonds with the oxygen atom in M341 and the nitrogen atom in G344 of SRC. In vitro experiments confirmed that AG reduced the viability of MDA-MB-453 and MDA-MB-231 cells in a concentration-and time-dependent manner, leading S phase arrest and apoptosis. Western blotting indicated that AG significantly reduced the levels of Bcl-2, caspase-3, and caspase-9, as well as decreased SRC, p-PI3K-p85, p-AKT1, p-MEK1/2, and p-ERK1/2 expression in TNBC cells in a concentration dependent manner.
Conclusion:
AG exerts anti-TNBC effects by directly binding to SRC kinase, concurrently inhibiting both PI3K/AKT and MEK/ERK signaling pathways, ultimately leading to cell cycle arrest and apoptosis.
Insights
Arctigenin (AG) shows therapeutic potential against triple-negative breast cancer (TNBC) by inhibiting SRC kinase. This action triggers cell cycle arrest and apoptosis, offering a new avenue for TNBC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted therapy options.
- Arctigenin (AG) is a natural compound with potential anti-cancer properties.
- Elucidating the molecular mechanisms of AG in TNBC is crucial for therapeutic development.
Purpose of the Study:
- To investigate the therapeutic efficacy of Arctigenin (AG) against triple-negative breast cancer (TNBC).
- To identify the molecular targets and pathways through which AG exerts its anti-TNBC effects.
- To validate the interaction of AG with key molecular targets using computational and experimental methods.
Main Methods:
- Bioinformatic analyses including target identification, differential gene expression, and Weighted Gene Co-expression Network Analysis (WGCNA).
- Machine learning algorithms for hub gene identification.
- Molecular docking, molecular dynamics (MD) simulations, and surface plasmon resonance (SPR) assays for target validation.
- In vitro experiments on TNBC cell lines (MDA-MB-453, MDA-MB-231) including cell viability, cell cycle, apoptosis assays, and Western blotting.
Main Results:
- Identification of 183 AG-related targets and key TNBC-associated genes.
- Machine learning identified 4 hub genes, with SRC kinase showing significant interaction with AG via molecular docking, MD, and SPR.
- In vitro studies demonstrated that AG inhibits TNBC cell viability, induces S phase arrest and apoptosis.
- AG treatment downregulated key proteins involved in cell survival and proliferation, including Bcl-2, SRC, PI3K/AKT, and MEK/ERK signaling pathways.
Conclusions:
- Arctigenin (AG) exhibits significant anti-TNBC activity.
- AG directly binds to SRC kinase, inhibiting its activity.
- The anti-cancer effects of AG are mediated through the concurrent inhibition of PI3K/AKT and MEK/ERK signaling pathways, leading to cell cycle arrest and apoptosis in TNBC cells.
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