近日，上海中医药大学季莉莉团队发现，异川楝素通过减少线粒体分裂和由Smad2/3-GOT2-MYH9信号轴调控的鳞状细胞形成抑制三阴性乳腺癌转移。相关论文于2024年7月15日在线发表在《中国药理学报》杂志上。

研究人员表示，三阴性乳腺癌（TNBC）是难以治愈且容易广泛转移的癌症。因此，识别TNBC进展的关键靶点是急需的。先前的研究表明，异川楝素（ITSN）通过靶向TGFβR1减少了TNBC的转移。

ITSN被研究人员用作有效的化学探针，以进一步发现参与TNBC转移的关键分子，这些分子位于TGFβR1下游。研究结果显示，GOT2是Smad2/3下游的基因，ITSN通过直接结合TGFβR1，阻断TGF-β-Smad2/3信号通路的激活，从而降低GOT2的表达。GOT2在TNBC中高表达，其敲除减少了TNBC的转移。然而，GOT2的过表达在体内和体外均逆转了ITSN对TNBC转移的抑制作用。GOT2与MYH9相互作用，并阻碍其与E3泛素连接酶STUB1的结合，从而减少MYH9的泛素化和降解。

此外，GOT2还增强了MYH9向线粒体的转运，从而诱导DRP1磷酸化，促进TNBC细胞中的线粒体分裂和伪足形成。ITSN介导的线粒体分裂和伪足形成的抑制与GOT2表达的减少有关。总之，ITSN通过减少GOT2表达，增强MYH9蛋白的降解，从而阻止MYH9调控的线粒体分裂和伪足形成，最终抑制TNBC的转移。

附：英文原文

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

Author: Zhang, Jing-nan, Zhang, Ze, Huang, Zhen-lin, Guo, Qian, Wu, Ze-qi, Ke, Chuang, Lu, Bin, Wang, Zheng-tao, Ji, Li-li

Issue&Volume: 2024-07-15

Abstract: 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.

DOI: 10.1038/s41401-024-01335-3

Source: https://www.nature.com/articles/s41401-024-01335-3