Lappaol F, an anticancer agent, inhibits YAP via transcriptional and post-translational regulation.
Pharm Biol
; 59(1): 619-628, 2021 Dec.
Article
in En
| MEDLINE
| ID: mdl-34010589
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 ANDMETHODS:
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.Key words
Full text:
1
Database:
MEDLINE
Main subject:
Transcription Factors
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Transcription, Genetic
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Benzofurans
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4-Butyrolactone
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Protein Processing, Post-Translational
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Cell Cycle Proteins
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Antineoplastic Agents, Phytogenic
Type of study:
Prognostic_studies
Limits:
Animals
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Female
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Humans
Language:
En
Year:
2021
Type:
Article