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Breast Cancer Research
Published in: Breast Cancer Research 1/2021

Open Access 01-12-2021 | Metastasis | Research article

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

Authors: Mengli Zhang, Mei Meng, Yuxi Liu, Jindan Qi, Zhe Zhao, Yingnan Qiao, Yanxing Hu, Wei Lu, Zhou Zhou, Peng Xu, Quansheng Zhou

Published in: Breast Cancer Research | Issue 1/2021

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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.
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Metadata
Title
Triptonide effectively inhibits triple-negative breast cancer metastasis through concurrent degradation of Twist1 and Notch1 oncoproteins
Authors
Mengli Zhang
Mei Meng
Yuxi Liu
Jindan Qi
Zhe Zhao
Yingnan Qiao
Yanxing Hu
Wei Lu
Zhou Zhou
Peng Xu
Quansheng Zhou
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2021
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-021-01488-7

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