Triptolide inhibits pancreatic cancer cell proliferation and migration via down-regulating PLAU based on network pharmacology of Tripterygium wilfordii Hook F

Abstract

Tripterygium wilfordii Hook F (TwHF) exhibits anti-tumor efficacy in pancreatic ductal adenocarcinoma (PDAC), however the pharmacological mechanisms are unclear due to complicated formulae and target genes. Using Traditional Chinese Medicine Systems Pharmacology and GeneCards databases, we performed a network pharmacology (NP) of TwHF and screened out 22 ingredients and 25 target genes associated with PDAC. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the 25 target genes were performed. Using STRING database, protein-protein interaction network of the 25 target genes was constructed, and indicated that triptolide (TL)-plasminogen activator urokinase (PLAU) as a potential target for PDAC treatment. Hence, in vitro experiments were performed and validated that TL inhibited PDAC cell proliferation and migration by suppressing PLAU expression. The results of Western blot suggested that PLAU activated endothelial-mesenchymal transition (EMT) progression. In two Gene Expression Omnibus datasets (GSE16515 and GSE28735), PLAU was up-regulated in tumor tissues, and PLAU overexpression was associated with poor overall survival of PDAC cohort of The Cancer Genome Atlas (P < 0.01). Immunohistochemistry illustrated that overexpression of PLAU protein was related to lymph node metastasis in 20 PDAC patients (P < 0.01). Based on NP of TwHF, we identified and validated that TL-PLAU could serve as a potential target for PDAC treatment.