Isotoosendanin exerts inhibition on triple-negative breast cancer through abrogating TGF- β-induced epithelial-mesenchymal transition via directly targeting TGF β R1

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

doi:10.1016/j.apsb.2023.05.006

Isotoosendanin exerts inhibition on triple-negative breast cancer through abrogating TGF- β-induced epithelial-mesenchymal transition via directly targeting TGF β R1

Acta Pharm Sin B. 2023 Jul;13(7):2990-3007. doi: 10.1016/j.apsb.2023.05.006. Epub 2023 May 12.

Authors

Jingnan Zhang¹, Ze Zhang¹, Zhenlin Huang¹, Manlin Li¹, Fan Yang¹, Zeqi Wu¹, Qian Guo¹, Xiyu Mei¹, Bin Lu¹, Changhong Wang¹, Zhengtao Wang¹, Lili Ji¹

Affiliation

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.

Abstract

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.

Keywords: Epithelial–mesenchymal transition; Invadopodia; Isotoosendanin; Metastasis; PD-L1; TGFβR1; TNBC; Tumor microenvironment.