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 Ch...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.展开更多
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)+1 种基金Fundamental Research Funds for the Central Universities(2021yjsCXCY086,2019kfyXMBZ024)the Technical Innovation Special Project of Hubei Province(2018ACA138).
文摘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.
