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Paris saponin VII,a Hippo pathway activator,induces autophagy and exhibits therapeutic potential against human breast cancer cells

查看全文 作　　者：Yu-chen [1,2]Xiang;Peng [1,3]Peng;Xue-wen [1,4]Liu;Xin [1,2]Jin;Jie [1,2]Shen;Te [2,4]Zhang;Liang [1,3]Zhang;Fang [1,2]Wan;Yu-liang [1,2]Ren;Qing-qing [3,4]Yu;Hu-zi [1,3,4]Zhao;Yuan [1,3,4]Si;Ying [1,2,3,4]Liu 高影响力作者 机构地区：[1]Laboratory of Molecular Target Therapy of Cancer,Institute of Basic Medical Sciences,Hubei University of Medicine,Shiyan 442000,China;[2]Hubei Key Laboratory of Wudang Local Chinese Medicine Research,Hubei University of Medicine,Shiyan 442000,China;[3]Hubei Key Laboratory of Embryonic Stem Cell Research,Hubei University of Medicine,Shiyan 442000,China;[4]Laboratory of Molecular Target Therapy of Cancer,Biomedical Research Institute,Hubei University of Medicine,Shiyan 442000,China高影响力机构 出　　处：《Acta Pharmacologica Sinica》索引2022年第43卷第6期,共13页高影响力期刊 基　　金：This work was supported by grants from the National Natural Science Foundation of China(Nos 82072928 and 81802387);the Foundation for Innovative Research Group of Hubei Provincial Department of Science and Technology(No.2021CFA071);the Foundation for Innovative Research Team of Hubei Provincial Department of Education(No.T201915);the Principal Investigator Grant of Hubei University of Medicine(No.HBMUPI201806);the Innovative Research Program for Graduates(No.YC2021004);the Faculty Development Grants from Hubei University of Medicine(No.2018QDJZR03);the Scientific and Technological Project of Shiyan City of Hubei Province(Nos 21Y08 and 21Y09);the National Training Program of Innovation and Entrepreneurship for Undergraduates(Nos 202110929001 and 202110929002). 摘　　要：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 IC_(50) values of 3.16,3.45,and 2.86μM,respectively,and suppressed their colony formation.PSVII(1.2-1.8μM)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. 关 键 词：anti cancer drug pharmacology AUTOPHAGY Chinese traditional medicine molecular docking Breast cancer Hippo pathway activator
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