Abstract
BackgroundSanguisorba officinalis, a popular Chinese herb, called DiYu, has been shown to inhibit the growth of many human cancer cell lines, including colorectal cancer cells. The aims of this study were to discover the active compound and molecular mechanism of S. officinalis against Wnt/β-catenin signaling pathway and develop Wnt inhibitors from natural products as anti-colorectal cancer agents.Methods1,4,6-Tri-O-galloyl-β-d-glucopyranose (TGG) was obtained by the preparative HPLC. The effect of DiYu on proliferation of NIH3T3 and HT29 was detected by MTT assay. Luciferase reporter assay was applied to investigate the activity of Wnt/β-catenin signaling in NIH3T3. The expression levels of mRNA and protein were detected by RT-PCR and western blot. Immunofluorescence assay was used to measure the level of β-catenin in cytoplasm and nucleus. Transcriptomic profiling study was performed to investigate the molecular mechanism of DiYu on the Wnt/β-catenin signaling pathway.ResultsTGG significantly inhibited the Wnt/β-catenin signaling pathway, down-regulated the expression of β-catenin and Wnt target genes (Dkk1, c-Myc, FGF20, NKD1, Survivin), up-regulated the levels of cleaved caspase3, cleaved PARP and ratio of Bax/Bcl-2, which may explain the apoptosis of HT29.ConclusionsOur study enhanced the discovery of the materials and elucidation of mechanisms that account for the anti-Wnt activity of natural inhibitor (DiYu) and identified the potential of TGG to be developed as anti-colorectal cancer drugs.
Highlights
Sanguisorba officinalis, a popular Chinese herb, called DiYu, has been shown to inhibit the growth of many human cancer cell lines, including colorectal cancer cells
aqueous extract of Sanguisorba officinalis (DY)-B was further purified through preparative HPLC eluting with 40% aqueous acetonitrile to afford the compound DYB4, which was identified as 1,4,6-triO-galloyl-β-d-glucopyranose (TGG) by 1H-NMR and 13C-NMR. 1H-NMR assigns the signals to the different protons of the molecule, 13C-NMR assigns the signals to the different carbon atoms of the molecule
Sanguisorba officinalis and the active component blocked Wnt/β‐catenin signaling pathway in NIH3T3 cells To identify the natural products from traditional medicine Sanguisorba officinalis that blocked the Wnt signaling pathway, wnt3a-treated NIH3T3 cells model is important for evaluating the drug effects on Wnt/βcatenin signaling pathway, which were transfected with top flash plasmid containing TCF/LEF regions [13] for the luciferase reporter assay
Summary
Sanguisorba officinalis, a popular Chinese herb, called DiYu, has been shown to inhibit the growth of many human cancer cell lines, including colorectal cancer cells. It was found that most mutations of Wnt/βcatenin signaling were caused by the dysfunction of Apc [4] or β-catenin [5]. The formation of WntFz-LRP6 complex together with the scaffolding protein Dishevelled (Dvl) leads to inhibition of β-catenin phosphorylation. These events result in the stabilization and accumulation of β-catenin, which travels to the nucleus engaging T cell factor/lymphoid enhancer factor (TCF/ LEF) [13] to activate Wnt target gene expression
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