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

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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.

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Fig. 1: ITSN decreased the expression of GOT2 that is a downstream gene regulated by Smad2/3.
Fig. 2: GOT2 overexpression markedly reversed the anti-metastatic effect of ITSN.
Fig. 3: GOT2 could directly interact with MYH9.
Fig. 4: The GOT2-mediated promotion of TNBC metastasis was dependent on MYH9.
Fig. 5: GOT2 reduced MYH9 protein degradation.
Fig. 6: GOT2 reduced MYH9 protein degradation by interfering with the binding of MYH9 to STUB1.
Fig. 7: GOT2 recruited MYH9 to mitochondria to promote mitochondrial fission and lamellipodia formation.

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Acknowledgements

We thank KangChen Bio-tech (China) for providing assistance with RNA sequencing. This work was financially supported by the “Young Qihuang Scholar” for Li-li Ji, National Natural Science Foundation of China (82273994), Program of Shanghai Academic Research Leader (23XD1404000) and the Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine (2023YZZ02).

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  1. These authors contributed equally: **g-nan Zhang, Ze Zhang

Authors and Affiliations

  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

    **g-nan Zhang, Ze Zhang, Zhen-lin Huang, Qian Guo, Ze-qi Wu, Chuang Ke, Bin Lu, Zheng-tao Wang & Li-li Ji

  2. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 311399, China

    **g-nan Zhang

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Contributions

LLJ and JNZ conceived and designed the study. LLJ supervised the study. JNZ and ZZ performed most of the experiments. ZLH, QG, ZQW, CK, and BL assisted in a subset of the experiments and helped with the data analysis. JNZ wrote the manuscript. LLJ and ZTW revised the manuscript. All of the authors contributed to this work and approved the final draft.

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Correspondence to Li-li Ji.

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Zhang, Jn., Zhang, Z., Huang, Zl. et al. Isotoosendanin inhibits triple-negative breast cancer metastasis by reducing mitochondrial fission and lamellipodia formation regulated by the Smad2/3-GOT2-MYH9 signaling axis. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01335-3

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