Triptonide effectively inhibits triple-negative breast cancer metastasis through concurrent degradation of Twist1 and Notch1 oncoproteins

Breast Cancer Research

Zhou Zhou¹  Yingnan Qiao¹  Wei Lu¹  Yuxi Liu¹  Yanxing Hu¹  Zhe Zhao¹  Mei Meng¹  Mengli Zhang¹  Peng Xu¹  Quansheng Zhou²  Jindan Qi³ 

[1] Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, 215123, Suzhou, Jiangsu, People’s Republic of China;Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, 215123, Suzhou, Jiangsu, People’s Republic of China;State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, 215123, Suzhou, Jiangsu, People’s Republic of China;National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, 215006, Suzhou, Jiangsu, People’s Republic of China;School of Nursing, Soochow University, 215006, Suzhou, Jiangsu, People’s Republic of China;

关键词: Breast cancer;    Metastasis;    Triptonide;    Twist1;    Notch1;   

DOI  :  10.1186/s13058-021-01488-7

来源: Springer

【 摘 要 】

BackgroundTriple-negative breast cancer (TNBC) is highly metastatic and lethal. Due to a lack of druggable targets for this disease, there are no effective therapies in the clinic.MethodsWe used TNBC cells and xenografted mice as models to explore triptonide-mediated inhibition of TNBC metastasis and tumor growth. Colony formation assay was used to quantify the tumorigenesis of TNBC cells. Wound-healing and cell trans-well assays were utilized to measure cell migration and invasion. Tube formation assay was applied to access tumor cell-mediated vasculogenic mimicry. Western blot, quantitative-PCR, immunofluorescence imaging, and immunohistochemical staining were used to measure the expression levels of various tumorigenic genes in TNBC cells.ResultsHere, we showed that triptonide, a small molecule from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, potently inhibited TNBC cell migration, invasion, and vasculogenic mimicry, and effectively suppressed TNBC tumor growth and lung metastasis in xenografted mice with no observable toxicity. Molecular mechanistic studies revealed that triptonide strongly triggered the degradation of master epithelial-mesenchymal transition (EMT)-inducing protein Twist1 through the lysosomal system and reduced Notch1 expression and NF-κB phosphorylation, which consequently diminished the expression of pro-metastatic and angiogenic genes N-cadherin, VE-cadherin, and vascular endothelial cell growth factor receptor 2 (VEGFR2).ConclusionsTriptonide effectively suppressed TNBC cell tumorigenesis, vasculogenic mimicry, and strongly inhibited the metastasis of TNBC via degradation of Twist1 and Notch1 oncoproteins, downregulation of metastatic and angiogenic gene expression, and reduction of NF-κB signaling pathway. Our findings provide a new strategy for treating highly lethal TNBC and offer a potential new drug candidate for combatting this aggressive disease.

【 授权许可】

CC BY