An isoflavone derivative potently inhibits the angiogenesis and progression of triple-negative breast cancer by targeting the MTA2/SerRS/VEGFA pathway  

作　　者：Xiaotong Zhang Gengyi Zou Xiyang Li Lun Wang Tianyu Xie Jin Zhao Longlong Wang Shunchang Jiao Rong Xiang Haoyu Ye Yi Shi 

机构地区：[1]School of Medicine,Nankai University,Tianjin 300071,China [2]2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education,Tianjin 300071,China [3]Department of Oncology,Chinese PLA General Hospital,Beijing 100853,China [4]State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,and Collaborative Innovation Center for Biotherapy,Chengdu 610041,China

出　　处：《Cancer Biology & Medicine》2020年第3期693-706,共14页癌症生物学与医学（英文版）

基　　金：This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81772974,81972882,and 81874297);the Bilateral Inter-Governmental S&T Cooperation Project from Ministry of Science and Technology of China(Grant No.2018YFE0114300);the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University.We thank Dr.Scott McKercher(The Scripps Research Institute,La Jolla,CA,USA);Dr.Phillip Bryant(Childrens Hospital of Philadelphia,PA,USA);Dr.Cameron R.McKay(Nankai University School of Medicine,Tianjin,China)for revising the manuscript.

摘　　要：Objective:Angiogenesis plays a vital role in tumor growth and metastasis.Here,we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A(VEGFA)at the transcriptional level to treat triple-negative breast cancer(TNBC).Methods:We used a cell-based seryl tRNA synthetase(SerRS)promoter-driven dual-luciferase reporter system to screen an in-house library of 384 naturally occurring small molecules and their derivatives to find candidate molecules that could upregulate the expression of SerRS,a potent transcriptional repressor of VEGFA.The levels of SerRS and VEGFA were examined by quantitative RT-PCR(qRT-PCR),western blotting,and/or ELISAs in TNBC cells after candidate molecule administration.Zebrafish,the Matrigel plug angiogenesis assay in mice,the TNBC allograft,and xenograft mouse models were used to evaluate thein vivoanti-angiogenic and anti-cancer activities.Furthermore,the potential direct targets of the candidates were identified by proteomics and biochemical studies.Results:We found the most active compound was 3-(4-methoxyphenyl)quinolin-4(1H)-one(MEQ),an isoflavone derivative.In TNBC cells,MEQ treatment resulted in increased SerRS mRNA(P<0.001)and protein levels and downregulated VEGFA production.Both the vascular development of zebrafish and Matrigel plug angiogenesis in mice were inhibited by MEQ.MEQ also suppressed the angiogenesis in TNBC allografts and xenografts in mice,resulting in inhibited tumor growth and prolonged overall survival(P<0.05).Finally,we found that MEQ regulated SerRS transcription by interacting with MTA2(Metastasis Associated 1 Family Member 2).Conclusions:Our findings suggested that the MTA2/SerRS/VEGFA axis is a drug-treatable anti-angiogenic target,and MEQ is a promising anti-tumor molecule that merits further investigation for clinical applications.

关 键 词：ISOFLAVONE MTA2 SERRS tumor angiogenesis VEGFA 

分 类 号：R737.9[医药卫生—肿瘤]