Exploring and validating the metastasis mechanism of pathenolide interfering with cutaneous melanoma through ER stress‐dependent apoptosis based on the network pharmacology

Abstract

BackgroundThis study aimed to explore the mechanism of parthenolide in inhibiting melanoma metastasis through network pharmacology and cell experiment.Materials and MethodsThis research obtained the targets of the drug from the HERB database and PubChem database, the differential expression gene of metastatic cutaneous melanoma was obtained by differentially expression gene analysis of four Gene Expression Omnibus (GEO) datasets. The intersection of drug targets and differentially expression genes were considered to be related to drugs that inhibit metastasis of cutaneous melanoma. The STRING database was used to construct the protein–protein interaction (PPI) network, and cytohubba package in Cytoscape software was used to rank the PPI network targets. The enrichment analysis was used to screen out the relevance Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology to explain the underlying mechanism of drug inhibiting the cutaneous melanoma metastatic; cell viability, apoptosis, cell migration and protein levels were assessed using cell counting kit‐8 (CCK‐8) assay, Annexin V‐FITC/PI assay, wound healing assay, respectively. Finally, combining pathway maps and literature, we detected ATF4 and proteins upstream and downstream of ATF4 through Western blot.ResultsA total of 87 targets were screened out from the drug databases, and a total of 1635 differentially expression genes was obtained from the differentially expression genes analysis of GEO datasets, a total of nine targets (VEGFA, ANXA5, ICAM1, SELE, NFKBIA, ATF4, CTNNB1, SELP and HPGDS) were considered to be related to drugs that inhibit metastasis of cutaneous melanoma. The result of enrichment analysis showed that the drug inhibits the metastatic of cutaneous melanoma through multiple pathways such as TNF signalling pathway, lipid and atherosclerosis and fluid shear stress and atherosclerosis, relevance multiple biological processes, cellular components and molecular function; cell experiments showed that parthenolide could inhibit tumour cell migration and induce a decrease of cell viability. Flow cytometry results showed that parthenolide induced tumour cell apoptosis. Western blot results suggested that parthenolide exerted therapeutic effects by regulating ATF4 protein and its upstream and downstream proteins, namely endoplasmic reticulum (ER) stress signalling pathway.ConclusionParthenolide induces ER stress‐dependent apoptosis in melanoma cells.

Parthenolide induces ROS-dependent cell death in human gastric cancer cell

“…Parthenolide (PN), a sesquiterpene lactone derived from feverfew, which is the traditional herbal medicine, has been found to exert multiple pharmacological effects such as antimicrobial, anti-inflammatory and anti-cancer effects. [1][2][3] These biological properties of PN may be attributed to its α-methylene-γ-lactone moiety. 4 At present, strong inhibition of nuclear factor NF-κB (nuclear factor kappa-light-chainenhancer of activated B cells) along the NF-κB signaling pathway in multiple steps makes PN the inhibitor of NF-κB.…”