The tumor-enriched small molecule gambogic amide suppresses glioma by targeting WDR1-dependent cytoskeleton remodeling  

作　　者：Jiaorong Qu Bojun Qiu Yuxin Zhang Yan Hu Zhixing Wang Zhiang Guan Yiming Qin Tongtong Sui Fan Wu Boyang Li Wei Han Xiaozhong Peng 

机构地区：[1]Department of Molecular Biology and Biochemistry,Institute of Basic Medical Sciences,Medical Primate Research Center,Neuroscience Center,Chinese Academy of Medical Sciences,School of Basic Medicine,Peking Union Medical College,Beijing 100005,China [2]State Key Laboratory of Common Mechanism Research for Major Diseases,Beijing,China [3]Department of Molecular Neuropathology,Beijing Neurosurgical Institute,Capital Medical University,Beijing 100070,China [4]Department of Neurosurgery,Beijing Tiantan Hospital,Capital Medical University,Beijing,China [5]State Key Laboratory of Respiratory Health and Multimorbidity,Beijing,China [6]National Human Diseases Animal Model Resource Center,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases,Institute of Laboratory Animal Science,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100021,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第12期5904-5918,共15页信号转导与靶向治疗（英文）

基　　金：supported by the CAMS Innovation Fund for Medical Sciences(CIFMS)grant(2021-I2M-1-034);the National Key R&D Program of China(2022YFC3401002);the National Natural Science Foundation of China(82173373).

摘　　要：Glioma is the most prevalent brain tumor,presenting with limited treatment options,while patients with malignant glioma and glioblastoma(GBM)have poor prognoses.The physical obstacle to drug delivery imposed by the blood‒brain barrier(BBB)and glioma stem cells(GSCs),which are widely recognized as crucial elements contributing to the unsatisfactory clinical outcomes.In this study,we found a small molecule,gambogic amide(GA-amide),exhibited the ability to effectively penetrate the blood-brain barrier(BBB)and displayed a notable enrichment within the tumor region.Moreover,GA-amide exhibited significant efficacy in inhibiting tumor growth across various in vivo glioma models,encompassing transgenic and primary patient-derived xenograft(PDX)models.We further performed a genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)knockout screen to determine the druggable target of GA-amide.By the combination of the cellular thermal shift assay(CETSA),the drug affinity responsive target stability(DARTS)approach,molecular docking simulation and surface plasmon resonance(SPR)analysis,WD repeat domain 1(WDR1)was identified as the direct binding target of GA-amide.Through direct interaction with WDR1,GA-amide promoted the formation of a complex involving WDR1,MYH9 and Cofilin,which accelerate the depolymerization of F-actin to inhibit the invasion of patient-derived glioma cells(PDCs)and induce PDC apoptosis via the mitochondrial apoptotic pathway.In conclusion,our study not only identified GA-amide as an effective and safe agent for treating glioma but also shed light on the underlying mechanisms of GA-amide from the perspective of cytoskeletal homeostasis.

关 键 词：GLIOMA invasion HOMEOSTASIS 

分 类 号：R739.4[医药卫生—肿瘤]