Synergistic induction of mitotic pyroptosis and tumor remission by inhibiting proteasome and WEE family kinases  

作　　者：Zhan-Li Chen Chen Xie Wei Zeng Rui-Qi Huang Jin-E Yang Jin-Yu Liu Ya-Jing Chen Shi-Mei Zhuang 

机构地区：[1]MOE Key Laboratory of Gene Function and Regulation,Guangdong Province Key Laboratory of Pharmaceutical Functional Genes,School of Life Sciences,State Key Laboratory of Oncology in Southern China,Sun Yat-sen University,Guangzhou,PR China [2]Key Laboratory of Liver Disease of Guangdong Province,The Third Affiliated Hospital,Sun Yat-sen University,Guangzhou 510630,PR China

出　　处：《Signal Transduction and Targeted Therapy》2024年第8期3467-3482,共16页信号转导与靶向治疗（英文）

基　　金：This study was supported by grants from National Key R&D Program of China(2019YFA0906001 to S.M.Z.);National Natural Science Foundation of China(81930076 to S.M.Z.,32000494 to C.X.);Guangdong Basic and Applied Basic Research Foundation(2023A1515012301 to C.X.);Guangzhou Basic Research Project(2023A04J1753 to C.X.)。

摘　　要：Mitotic catastrophe(MC),which occurs under dysregulated mitosis,represents a fascinating tactic to specifically eradicate tumor cells.Whether pyroptosis can be a death form of MC remains unknown.Proteasome-mediated protein degradation is crucial for M-phase.Bortezomib(BTZ),which inhibits the 20S catalytic particle of proteasome,is approved to treat multiple myeloma and mantle cell lymphoma,but not solid tumors due to primary resistance.To date,whether and how proteasome inhibitor affected the fates of cells in M-phase remains unexplored.Here,we show that BTZ treatment,or silencing of PSMC5,a subunit of 19S regulatory particle of proteasome,causes G2-and M-phase arrest,multi-polar spindle formation,and consequent caspase-3/GSDME-mediated pyroptosis in M-phase(designated as mitotic pyroptosis).Further investigations reveal that inhibitor of WEE1/PKMYT1(PD0166285),but not inhibitor of ATR,CHK1 or CHK2,abrogates the BTZ-induced G2-phase arrest,thus exacerbates the BTZ-induced mitotic arrest and pyroptosis.Combined BTZ and PD0166285 treatment(named BP-Combo)selectively kills various types of solid tumor cells,and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 monotreatment.Studies using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment,and no obvious toxicity is observed in BP-Combo-treated mice.These findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase,characterize pyroptosis as a new death form of mitotic catastrophe,and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.

关 键 词：PROTEASOME INHIBITING CATASTROPHE 

分 类 号：R73[医药卫生—肿瘤]