Isotoosendanin inhibits triple-negative breast cancer metastasis by reducing mitochondrial fission and lamellipodia formation regulated by the Smad2/3-GOT2-MYH9 signaling axis  

作　　者：Jing-nan Zhang Ze Zhang Zhen-lin Huang Qian Guo Ze-qi Wu Chuang Ke Bin Lu Zheng-tao Wang Li-li 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 [2]School of Pharmaceutical Sciences,Hangzhou Medical College,Hangzhou 311399,China

出　　处：《Acta Pharmacologica Sinica》2024年第12期2672-2683,共12页中国药理学报（英文版）

基　　金：supported by the"Young Qihuang Scholar"for Li-li Ji,National Natural Science Foundation of China(82273994);Program of Shanghai Academic Research Leader(23XD1404000);the Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(2023YZZ02).

摘　　要：Triple-negative breast cancer(TNBC)is incurable and prone to widespread metastasis.Therefore,identification of key targets for TNBC progression is urgently needed.Our previous study revealed that isotoosendanin(ITSN)reduced TNBC metastasis by targeting TGFβR1.ITSN is currently used as an effective chemical probe to further discover the key molecules involved in TNBC metastasis downstream of TGFβR1.The results showed that GOT2 was the gene downstream of Smad2/3 and that ITSN decreased GOT2 expression by abrogating the activation of the TGF-β-Smad2/3 signaling pathway through directly binding to TGFβR1.GOT2 was highly expressed in TNBC,and its knockdown decreased TNBC metastasis.However,GOT2 overexpression reversed the inhibitory effect of ITSN on TNBC metastasis both in vitro and in vivo.GOT2 interacted with MYH9 and hindered its binding to the E3 ubiquitin ligase STUB1,thereby reducing MYH9 ubiquitination and degradation.Moreover,GOT2 also enhanced the translocation of MYH9 to mitochondria and thus induced DRP1 phosphorylation,thereby promoting mitochondrial fission and lamellipodia formation in TNBC cells.ITSN-mediated inhibition of mitochondrial fission and lamellipodia formation was associated with reduced GOT2 expression.In conclusion,ITSN prevented MYH9-regulated mitochondrial fission and lamellipodia formation in TNBC cells by enhancing MYH9 protein degradation through a reduction in GOT2 expression,thus contributing to its inhibition of TNBC metastasis.

关 键 词：TNBC isotoosendanin GOT2 MYH9 DRP1 mitochondrial fission 

分 类 号：R737.9[医药卫生—肿瘤]