Paris saponinⅦinduces Caspase-3/GSDME-dependent pyroptosis in pancreatic ductal adenocarcinoma cells by activating ROS/Bax signaling  

作　　者：Xiaoying Qian Yang Liu Wenwen Chen Shuxian Zheng Yunyang Lu Pengcheng Qiu Xisong Ke Haifeng Tang Xue Zhang 

机构地区：[1]Center for Chemical Biology,Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China [2]Department of Chinese Materia Medica and Natural Medicines,School of Pharmacy,Air Force Medical University,Xi’an 710032,China [3]School of Pharmacy,Shaanxi University of Chinese Medicine,Xianyang 712046,China

出　　处：《Chinese Herbal Medicines》2025年第1期94-107,共14页中草药(英文版)

基　　金：supported by the National Natural Science Foundation of China(No.81973192)。

摘　　要：Objective:Paridis Rhizoma(Chonglou in Chinese),a traditional Chinese herbal medicine,has been shown have strong anti-tumor effects.Paris saponinⅦ(PSⅦ),an active constituent isolated from Paridis Rhizoma,was demonstrated to significantly suppress the proliferation of BxPC-3 cells in our previous study.Here,we aimed to elucidate the anti-pancreatic ductal adenocarcinoma(PDAC)effect of PSⅦand the underlying mechanism.Methods:Cell viability was determined by CCK-8,colony formation,and cell migration assays.Cell apoptosis and reactive oxygen species(ROS)production were measured by flow cytometry with annexin V/propidine iodide(Annexin V/PI)and 2',7'-dichlorodihydrofluorescein diacetate(DCFH-DA),respectively.Pyroptosis was evaluated by morphological features,Hoechst 33342/PI staining assay,and release of lactate dehydrogenase(LDH).JC-1 fluorescent dye was employed to measure mitochondrial membrane potential.Western blotting and reverse transcription-quantitative polymerase chain reaction(RT-qPCR)were used to determine the levels of proteins or mRNAs.The effect in vivo was assessed by a xenograft tumor model.Results:PSⅦinhibited the viability of PDAC cells(BxPC-3,PANC-1,and Capan-2 cells)and induced gasdermin E(GSDME)cleavage,as well as the simultaneous cleavage of Caspase-3 and poly(ADP-ribose)polymerase 1(PARP).Knockdown of GSDME shifted PSⅦ-induced pyroptosis to apoptosis.Additionally,the effect of PSⅦwas significantly attenuated by Z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fl uoromethylketone(Z-DEVD-FMK),on the induction of GSDME-dependent pyroptosis.PSⅦalso elevated intracellular ROS accumulation and stimulated Bax and Caspase-3/GSDME to conduct pyroptosis in PDAC cells.The ROS scavenger N-acetyl cysteine(NAC)suppressed the release of LDH and inhibited Caspase-9,Caspase-3,and GSDME cleavage in PDAC cells,ultimately reversing PSⅦ-induced pyroptosis.Furthermore,in a xenograft tumor model,PSⅦmarkedly suppressed the growth of PDAC tumors and induced pyroptosis.Conclusion:These results demonstrated that PSⅦex

关 键 词：CASPASE-3 gasdermin E pancreatic ductal adenocarcinoma paris saponin VII PYROPTOSIS reactive oxygen species 

分 类 号：R285[医药卫生—中药学]