A high-throughput Gaussia luciferase reporter assay for screening potential gasdermin E activators against pancreatic cancer  

作　　者：Yang Liu Xiaowei Zhang Ping Zhang Tingting He Weitao Zhang Dingyuan Ma Ping Li Jun Chen 

机构地区：[1]State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 210009,China [2]Department of Pharmacognosy,School of Traditional Chinese Pharmacy,China Pharmaceutical University,Nanjing 211198,China [3]Department of Prenatal Diagnosis,Nanjing Maternity and Child Health Care Hospital,Women’s Hospital of Nanjing Medical University,Nanjing 210004,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第10期4253-4272,共20页药学学报（英文版）

基　　金：financially supported by the National Natural Science Foundation of China(No.82174100);the National Key R&D Program of China(No.2022YFC3501601)。

摘　　要：It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E(GSDME)-deficient cells,but pyroptosis in GSDME-sufficient cells.The high GSDME expression and apoptosis resistance of pancreatic ductal adenocarcinoma(PDAC)cells shed light on another attractive strategy for PDAC treatment by promoting pyroptosis.Here we report a hGLuc-hGSDME-PCA system for high-throughput screening of potential GSDME activators against PDAC.This screening system neatly quantifies the oligomerization of GSDME-N to characterize whether pyroptosis occurs under the stimulation of chemotherapy drugs.Based on this system,ponatinib and perifosine are screened out from the FDA-approved anti-cancer drug library containing 106 compounds.Concretely,they exhibit the most potent luminescent activity and cause drastic pyroptosis in PDAC cells.Further,we demonstrate that perifosine suppresses pancreatic cancer by promoting pyroptosis via caspase-3/GSDME pathway both in vitro and in vivo.Collectively,this study reveals the great significance of hGLuc-hGSDME-PCA in identifying compounds triggering GSDME-dependent pyroptosis and developing promising therapeutic agents for PDAC.

关 键 词：PYROPTOSIS Caspase-3 Gasdermin E Pancreatic ductal adenocarcinoma hGLuc-hGSDME-PCA High-throughput screening PONATINIB PERIFOSINE 

分 类 号：R91[医药卫生—药学]