Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation  

作　　者：Guan-Nan Li Xue-Jiao Zhao Zhen Wang Meng-Shi Luo Shen-Nan Shi Dan-Mei Yan Hua-Yi Li Jia-Hao Liu Yang Yang Jia-Hong Tan Ze-Yu Zhang Ru-Qi Chen Hui-Ling Lai Xiao-Yuan Huang Jian-Feng Zhou Ding Ma Yong Fang Qing-Lei Gao 

机构地区：[1]Cancer Biology Research Center(Key Laboratory of the Ministry of Education),Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,430030 Wuhan,Hubei,China [2]National Clinical Research Center for Obstetrics and Gynecology,Department of Gynecological Oncology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,430030 Wuhan,Hubei,China [3]Department of Hematology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,430030 Wuhan,Hubei,China [4]Department of Gynecology,the Sixth Affiliated Hospital,Sun Yat-Sen University,510000 Guangzhou,Guangdong,China

出　　处：《Signal Transduction and Targeted Therapy》2022年第10期3925-3939,共15页信号转导与靶向治疗（英文）

基　　金：funded by the National Science and Technology Major Sub-Project(2018ZX10301402-002);National Natural Science Foundation of China(81772787,82072889,81602291,81874109,82072894);Fundamental Research Funds for the Central Universities(2021yjsCXCY086,2019kfyXMBZ024);the Technical Innovation Special Project of Hubei Province(2018ACA138).

摘　　要：Finely tuned mitogen-activated protein kinase(MAPK)signaling is important for cancer cell survival.Perturbations that push cells out of the MAPK fitness zone result in cell death.Previously,in a screen of the North China Pharmaceutical Group Corporation’s pure compound library of microbial origin,we identified elaiophylin as an autophagy inhibitor.Here,we demonstrated a new role for elaiophylin in inducing excessive endoplasmic reticulum(ER)stress,ER-derived cytoplasmic vacuolization,and consequent paraptosis by hyperactivating the MAPK pathway in multiple cancer cells.Genome-wide CRISPR/Cas9 knockout library screening identified SHP2,an upstream intermediary of the MAPK pathway,as a critical target in elaiophylin-induced paraptosis.The cellular thermal shift assay(CETSA)and surface plasmon resonance(SPR)assay further confirmed the direct binding between the SHP2 and elaiophylin.Inhibition of the SHP2/SOS1/MAPK pathway through SHP2 knockdown or pharmacological inhibitors distinctly attenuated elaiophylin-induced paraptosis and autophagy inhibition.Interestingly,elaiophylin markedly increased the alreadyelevated MAPK levels and preferentially killed drug-resistant cells with enhanced basal MAPK levels.Elaiophylin overcame drug resistance by triggering paraptosis in multiple tumor-bearing mouse models resistant to platinum,taxane,or PARPi,suggesting that elaiophylin might offer a reasonable therapeutic strategy for refractory ovarian cancer.

关 键 词：cancer activation ELEVATED 

分 类 号：R737.31[医药卫生—肿瘤]