Flavokawain C inhibits proliferation and migration of liver cancer cells through FAK/PI3K/AKT signaling pathway.

ABSTRACT

PURPOSE: This study investigated the potential applicability and the underlying mechanisms of flavokawain C, a natural compound derived from kava extracts, in liver cancer treatment. METHODS: Drug distribution experiment used to demonstrate the preferential tissues enrichment of flavokawain C. Cell proliferation, apoptosis and migration effect of flavokawain C were determined by MTT, colony formation, EdU staining, cell adhesion, transwell, flow cytometry and western blot assay. The mechanism was explored by comet assay, immunofluorescence assay, RNA-seq-based Kyoto encyclopedia of genes and genomes analysis, molecular dynamics, bioinformatics analysis and western blot assay. The anticancer effect of flavokawain C was further confirmed by xenograft tumor model. RESULTS: The studies first demonstrated the preferential enrichment of flavokawain C within liver tissues in vivo. The findings demonstrated that flavokawain C significantly inhibited proliferation and migration of liver cancer cells, induced cellular apoptosis, and triggered intense DNA damage along with strong DNA damage response. The findings from RNA-seq-based KEGG analysis, molecular dynamics, bioinformatics analysis, and western blot assay mechanistically indicated that treatment with flavokawain C notably suppressed the FAK/PI3K/AKT signaling pathway in liver cancer cells. This effect was attributed to the induction of gene changes and the binding of flavokawain C to the ATP sites of FAK and PI3K, resulting in the inhibition of their phosphorylation. Additionally, flavokawain C also displayed the strong capacity to inhibit Huh-7-derived xenograft tumor growth in mice with minimal adverse effects. CONCLUSIONS: These findings identified that flavokawain C is a promising anticancer agent for liver cancer treatment.