Lappaol F, an anticancer agent, inhibits YAP via transcriptional and post-translational regulation

Context: Lappaol F (LAF), a natural lignan from Arctium lappa Linné (Asteraceae), inhibits tumour cell growth by inducing cell cycle arrest. However, its underlying Anticancer mechanism remains unclear.

Objective: The effects of LAF on the Hippo-Yes-associated protein (YAP) signalling pathway, which plays an important role in Cancer progression, were explored in this study.

Materials and methods: Cervical (HeLa), colorectal (SW480), breast (MDA-MB-231) and prostate (PC3) Cancer cell lines were treated with LAF at different concentrations and different durations. BALB/c nude mice bearing colon xenografts were intravenously injected with vehicle, LAF (10 or 20 mg/kg) or paclitaxel (10 mg/kg) for 15 days. The expression and nuclear localisation of YAP were analysed using transcriptome sequencing, quantitative PCR, western blotting and immunofluorescence.

Results: LAF suppressed the proliferation of HeLa, MDA-MB-231, SW480 and PC3 cells (IC₅₀ values of 41.5, 26.0, 45.3 and 42.9 μmol/L, respectively, at 72 h), and this was accompanied by significant downregulation in the expression of YAP and its downstream target genes at both the mRNA and protein levels. The expression of 14-3-3σ, a protein that causes YAP cytoplasmic retention and degradation, was remarkably increased, resulting in a decrease in YAP nuclear localisation. Knockdown of 14-3-3σ with small interfering RNA partially blocked LAF-induced YAP inhibition and anti-proliferation effects. In colon xenografts, treatment with LAF led to reduced YAP expression, increased tumour cell Apoptosis and tumour growth inhibition.

Conclusion: LAF was shown to be an inhibitor of YAP. It exerts Anticancer activity by inhibiting YAP at the transcriptional and post-translational levels.

14-3-3σ; Yes-associated protein; apoptosis; cell proliferation; colon xenografts; tumour suppression.