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

Content Provider	Springer Nature : BioMed Central
Author	Zhang, Mengli Meng, Mei Liu, Yuxi Qi, Jindan Zhao, Zhe Qiao, Yingnan Hu, Yanxing Lu, Wei Zhou, Zhou Xu, Peng Zhou, Quansheng
Abstract	Background Triple-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. Methods We 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. Results Here, 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). Conclusions Triptonide 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.
Related Links	https://breast-cancer-research.biomedcentral.com/counter/pdf/10.1186/s13058-021-01488-7.pdf
Ending Page	16
Page Count	16
Starting Page	1
File Format	HTM / HTML
DOI	10.1186/s13058-021-01488-7
Journal	Breast Cancer Research
Issue Number	1
Volume Number	23
Language	English
Publisher	BioMed Central
Publisher Date	2021-12-18
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Surgical Oncology Breast cancer Metastasis Triptonide Twist1 Notch1
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	7.1/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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