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.

Yu-chen Xiang;Peng Peng;Xue-wen Liu;Xin Jin;Jie Shen;Te Zhang;Liang Zhang;Fang Wan;Yu-liang Ren;Qing-qing Yu;Hu-zi Zhao;Yuan Si;Ying Liu

Laboratory of Molecular Target Therapy of Cancer,Institute of Basic Medical Sciences,Hubei University of Medicine,Shiyan 442000,China;Hubei Key Laboratory of Wudang Local Chinese Medicine Research,Hubei University of Medicine,Shiyan 442000,China;Hubei Key Laboratory of Embryonic Stem Cell Research,Hubei University of Medicine,Shiyan 442000,China;Laboratory of Molecular Target Therapy of Cancer,Biomedical Research Institute,Hubei University of Medicine,Shiyan 442000,China

中国药理学报（英文版）

[1]Yu-chen Xiang;Peng Peng;Xue-wen Liu;Xin Jin;Jie Shen;Te Zhang;Liang Zhang;Fang Wan;Yu-liang Ren;Qing-qing Yu;Hu-zi Zhao;Yuan Si;Ying Liu-.Paris saponin Ⅶ,a Hippo pathway activator,induces autophagy and exhibits therapeutic potential against human breast cancer cells)[J].中国药理学报（英文版）,2022(06):1568-1580

pLATS1

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