Abstract

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.

中文翻译：

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Lappaol F 是一种抗癌剂，通过转录和翻译后调节抑制 YAP

摘要

语境

Lappaol F (LAF) 是一种来自Arctium lappa Linné（菊科）的天然木脂素，通过诱导细胞周期停滞来抑制肿瘤细胞生长。然而，其潜在的抗癌机制仍不清楚。

客观的

本研究探讨了 LAF 对 Hippo-Yes 相关蛋白 (YAP) 信号通路的影响，该通路在癌症进展中起重要作用。

材料和方法

用不同浓度和不同持续时间的 LAF 处理宫颈 (HeLa)、结肠直肠 (SW480)、乳腺癌 (MDA-MB-231) 和前列腺 (PC3) 癌细胞系。携带结肠异种移植物的 BALB/c 裸鼠静脉注射赋形剂、LAF（10 或 20 毫克/千克）或紫杉醇（10 毫克/千克），持续 15 天。使用转录组测序、定量 PCR、蛋白质印迹和免疫荧光分析 YAP 的表达和核定位。

结果

LAF 抑制 HeLa、MDA-MB-231、SW480 和 PC3 细胞的增殖（IC ₅₀值分别为 41.5、26.0、45.3 和 42.9 μmol/L，在 72 小时时），并且伴随着表达的显着下调YAP 及其下游靶基因的 mRNA 和蛋白质水平。导致 YAP 细胞质滞留和降解的蛋白质 14-3-3σ 的表达显着增加，导致 YAP 核定位减少。用小干扰 RNA 敲除 14-3-3σ 部分阻断了 LAF 诱导的 YAP 抑制和抗增殖作用。在结肠异种移植物中，LAF 治疗导致 YAP 表达降低、肿瘤细胞凋亡增加和肿瘤生长抑制。

结论

LAF 被证明是 YAP 的抑制剂。它通过在转录和翻译后水平抑制 YAP 来发挥抗癌活性。