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Network pharmacology-based identification of the antitumor effects of taraxasterol in gastric cancer.

ABSTRACT: Taraxasterol (TAX), a pentacyclic triterpene, has been reported to exhibit potent antitumor activity. However, the effects and molecular mechanisms of TAX in gastric cancer (GC) remain undocumented. A network pharmacology approach was applied to identify the collective targets of TAX and GC. Nude mice were subcutaneously injected with MKN-28 cells to establish GC subcutaneous xenograft model, which were treated with TAX for 16?days. Tumor volume was then examined every other day. The pathological scoring was assessed by using hematoxylin and eosin (H&E) staining, and the expression levels of Ki-67 and the target genes of TAX were confirmed by immunohistochemistry analysis. Five collective targets of TAX and GC were identified, such as epidermal growth factor receptor (EGFR), matrix metalloproteinase 2 (MMP2), B-Raf proto-oncogene, serine/threonine kinase (BRAF), fibroblast growth factor receptor 2 (FGFR2), and AKT serine/threonine kinase 1 (AKT1). Further investigations showed that, TAX administration repressed xenograft tumor growth and decreased Ki-67 levels, followed by the downregulation of EGFR and AKT1 expression in xenograft tumor tissues as compared with the untreated group. Our findings demonstrated that TAX inhibited the growth of GC by inhibition of EGFR/AKT1 signaling and might provide a novel therapeutic strategy for treatment of GC.

SUBMITTER: Chen W

PROVIDER: S-EPMC7378706 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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Network pharmacology-based identification of the antitumor effects of taraxasterol in gastric cancer.

Chen Wei W Li Jingwei J Li Chen C Fan Hui-Ning HN Zhang Jing J Zhu Jin-Shui JS

International journal of immunopathology and pharmacology 20200101

Taraxasterol (TAX), a pentacyclic triterpene, has been reported to exhibit potent antitumor activity. However, the effects and molecular mechanisms of TAX in gastric cancer (GC) remain undocumented. A network pharmacology approach was applied to identify the collective targets of TAX and GC. Nude mice were subcutaneously injected with MKN-28 cells to establish GC subcutaneous xenograft model, which were treated with TAX for 16 days. Tumor volume was then examined every other day. The pathologica ...[more]

PMID: 32701378

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Project description:BackgroundGastric cancer (GC) is one of the most aggressive malignancies with limited therapeutic options and a poor prognosis. Resveratrol, a non-flavonoid polyphenolic compound found in a variety of Chinese medicinal materials, has shown excellent anti-GC effect. However, its exact mechanisms of action in GC have not been clarified.AimTo identify the effects of resveratrol on GC progression and explore the related molecular mechanisms.MethodsAction targets of resveratrol and GC-related targets were screened from public databases. The overlapping targets between the two were confirmed using a Venn diagram, and a "Resveratrol-Target-GC" network was constructed using Cytoscape software version 3.9.1. The protein-protein interaction (PPI) network was constructed using STRING database and core targets were identified by PPI network analysis. The Database for Annotation, Visualization and Integrated Discovery database was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A "Target-Pathway" network was created by using Cytoscape 3.9.1. The RNA and protein expression levels of core target genes were observed using the Cancer Genome Atlas and the Human Protein Atlas databases. DriverDBv3 and Timer2.0 databases were used for survival and immune infiltration analysis. Subsequently, the findings were further verified by molecular docking technology and in vitro experiments.ResultsA total of 378 resveratrol action targets and 2154 GC disease targets were obtained from public databases, and 181 intersection targets between the two were screened by Venn diagram. The top 20 core targets were identified by PPI network analysis of the overlapping targets. GO function analysis mainly involved protein binding, identical protein binding, cytoplasm, nucleus, negative regulation of apoptotic process and response to xenobiotic stimulus. KEGG enrichment analysis suggested that the involved signaling pathways mainly included PI3K-AKT signaling pathway, MAPK signaling pathway, IL-17 signaling pathway, TNF signaling pathway, ErbB signaling pathway, etc. FBJ murine osteosarcoma viral oncogene homolog (FOS) and matrix metallopeptidase 9 (MMP9) were selected by differential expression analysis, and they were closely associated with immune infiltration. Molecular docking results showed that resveratrol docked well with these two targets. Resveratrol treatment arrested the cell cycle at the S phase, induced apoptosis, and weakened viability, migration and invasion in a dose-dependent manner. Furthermore, resveratrol could exhibit anti-GC effect by regulating FOS and MMP9 expression.ConclusionThe anti-GC effects of resveratrol are related to the inhibition of cell proliferation, migration, invasion and induction of cell cycle arrest and apoptosis by targeting FOS and MMP9.

Dataset Information

Network pharmacology-based identification of the antitumor effects of taraxasterol in gastric cancer.

Publications

Network pharmacology-based identification of the antitumor effects of taraxasterol in gastric cancer.

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