Isotoosendanin exerts inhibition on triple-negative breast cancer through abrogating TGF-β-induced epithelial—mesenchymal transition via directly targeting TGFβR1  

作　　者：Jingnan Zhang Ze Zhang Zhenlin Huang Manlin Li Fan Yang Zeqi Wu Qian Guo Xiyu Mei Bin Lu Changhong Wang Zhengtao Wang Lili Ji 

机构地区：[1]The MOE Key Laboratory for Standardization of Chinese Medicines,Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines,Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第7期2990-3007,共18页药学学报（英文版）

基　　金：financially supported by the National Natural Science Foundation of China(82273994);the leadership in the Science and National Key Research and Development Program of China(2018YFC1707302)。

摘　　要：As the most aggressive breast cancer,triple-negative breast cancer(TNBC) is still incurable and very prone to metastasis.The transform growth factor β(TGF-β)-induced epithelial—mesenchymal transition(EMT) is crucially involved in the growth and metastasis of TNBC.This study reported that a natural compound isotoosendanin(ITSN) reduced TNBC metastasis by inhibiting TGF-β-induced EMT and the formation of invadopodia.ITSN can directly interact with TGF-β receptor type-1(TGFβR1) and abrogated the kinase activity of TGFβR1,thereby blocking the TGF-β-initiated downstream signaling pathway.Moreover,the ITSN-provided inhibition on metastasis obviously disappeared in TGFβR1-overexpressed TNBC cells in vitro as well as in mice bearing TNBC cells overexpressed TGFβR1.Furthermore,Lys232 and Asp351 residues in the kinase domain of TGFβR1 were found to be crucial for the interaction of ITSN with TGFβR1.Additionally,ITSN also improved the inhibitory efficacy of programmed cell death 1 ligand 1(PD-L1) antibody for TNBC in vivo via inhibiting the TGF-β-mediated EMT in the tumor microenvironment.Our findings not only highlight the key role of TGFβR1 in TNBC metastasis,but also provide a leading compound targeting TGFβR1 for the treatment of TNBC metastasis.Moreover,this study also points out a potential strategy for TNBC treatment by using the combined application of anti-PD-L1 with a TGFβR1 inhibitor.

关 键 词：TNBC Isotoosendanin METASTASIS TGFβR1 Epithelial-mesenchymal transition INVADOPODIA PD-L1 Tumor microenvironment 

分 类 号：R737.9[医药卫生—肿瘤]