A Novel Caffeoylquinic Acid from Lonicera japonica Exerts Cytotoxic Activity by Blocking the YAP-CTGF Signaling Pathway in Hepatocellular Carcinoma

Abstract

Abstract We have purified a novel caffeoylquinic acid named 3,4-di-O-caffeoylquinic acid isobutyl ester from the flower buds of Lonicera japonica Thunb., Caprifoliaceae. However, the biological function of 3,4-di-O-caffeoylquinic acid isobutyl ester is still unknown. Here, we found that 3,4-di-O-caffeoylquinic acid isobutyl ester effectively inhibited the proliferation and migration of hepatocellular carcinoma cells, and it displayed less toxicity to a normal liver cell line. Mechanistic studies showed that 3,4-di-O-caffeoylquinic acid isobutyl ester diminished the expression of YAP at the mRNA level. Overexpression of YAP significantly rescued HepG2 cells from the 3,4-di-O-caffeoylquinic acid isobutyl ester–induced suppression of proliferation and migration. Furthermore, the YAP downstream target gene CTGF was significantly repressed upon 3,4-di-O-caffeoylquinic acid isobutyl ester treatment, which was ameliorated by YAP overexpression. In addition, 3,4-di-O-caffeoylquinic acid isobutyl ester decreased the expression of β-catenin as well as CDK4/6. Collectively, 3,4-di-O-caffeoylquinic acid isobutyl ester exerts antihepatocellular carcinoma activity by inhibiting the YAP-CTGF pathway which controls the proliferation and migration of hepatocellular carcinoma cells. The Wnt/β-catenin pathway might be another pathway by which 3,4-di-O-caffeoylquinic acid isobutyl ester exerts antihepatocellular carcinoma activity. As a novel natural compound, 3,4-di-O-caffeoylquinic acid isobutyl ester might be a promising agent for hepatocellular carcinoma therapy. Graphical Abstract