Paris saponin VII, a Hippo pathway activator, induces autophagy and exhibits therapeutic potential against human breast cancer cells
- 14 September 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Pharmacologica Sinica
- Vol. 43 (6), 1568-1580
- https://doi.org/10.1038/s41401-021-00755-9
Abstract
Dysregulation of the Hippo signaling pathway seen in many types of cancer is usually associated with a poor prognosis. Paris saponin VII (PSVII) is a steroid saponin isolated from traditional Chinese herbs with therapeutic action against various human cancers. In this study we investigated the effects of PSVII on human breast cancer (BC) cells and its anticancer mechanisms. We showed that PSVII concentration-dependently inhibited the proliferation of MDA-MB-231, MDA-MB-436 and MCF-7 BC cell lines with IC50 values of 3.16, 3.45, and 2.86 μM, respectively, and suppressed their colony formation. PSVII (1.2–1.8 μM) induced caspase-dependent apoptosis in the BC cell lines. PSVII treatment also induced autophagy and promoted autophagic flux in the BC cell lines. PSVII treatment decreased the expression and nuclear translocation of Yes-associated protein (YAP), a downstream transcriptional effector in the Hippo signaling pathway; overexpression of YAP markedly attenuated PSVII-induced autophagy. PSVII-induced, YAP-mediated autophagy was associated with increased active form of LATS1, an upstream effector of YAP. The activation of LATS1 was involved the participation of multiple proteins (including MST2, MOB1, and LATS1 itself) in an MST2-dependent sequential activation cascade. We further revealed that PSVII promoted the binding of LATS1 with MST2 and MOB1, and activated LATS1 in the BC cell lines. Molecular docking showed that PSVII directly bound to the MST2-MOB1-LATS1 ternary complex. Microscale thermophoresis analysis and drug affinity responsive targeting stability assay confirmed the high affinity between PSVII and the MST2-MOB1-LATS1 ternary complex. In mice bearing MDA-MB-231 cell xenograft, administration of PSVII (1.5 mg/kg, ip, 4 times/week, for 4 weeks) significantly suppressed the tumor growth with increased pLATS1, LC3-II and Beclin 1 levels and decreased YAP, p62 and Ki67 levels in the tumor tissue. Overall, this study demonstrates that PSVII is a novel and direct Hippo activator that has great potential in the treatment of BC.Keywords
This publication has 52 references indexed in Scilit:
- Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathwayNature, 2015
- Phosphorylation of LC3 by the Hippo Kinases STK3/STK4 Is Essential for AutophagyMolecular Cell, 2014
- Paris saponin VII suppressed the growth of human cervical cancer Hela cellsEuropean Journal of Medical Research, 2014
- Paris saponin VII inhibits growth of colorectal cancer cells through Ras signaling pathwayBiochemical Pharmacology, 2014
- Metformin impairs growth of endometrial cancer cells via cell cycle arrest and concomitant autophagy and apoptosisCancer Cell International, 2014
- Simultaneous determination and pharmacokinetic study of polyphyllin I, polyphyllin II, polyphyllin VI and polyphyllin VII in beagle dog plasma after oral administration of Rhizoma Paridis extracts by LC‐MS‐MSBiomedical Chromatography, 2012
- AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1Nature, 2011
- Chemical study and medical application of saponins as anti-cancer agentsFitoterapia, 2010
- Protein-binding assays in biological liquids using microscale thermophoresisNature Communications, 2010
- Chapter 12 Monitoring Autophagic Degradation of p62/SQSTM1Methods in Enzymology, 2009