ReferenceID 6445
Triptonide effectively inhibits triple-negative breast cancer metastasis through concurrent degradation of Twist1 and Notch1 oncoproteins
Breast Cancer Res
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 xenog
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- Reference Id
- 6445
- Evidence Id
- 23035
- Core Evidence Id
- 23035
- Source Reference Id
- 6176
- Herb2 Reference Id
- HBREF006973
- Subject Paper Key
- HBIN047177_34922602
- Pubmed Id
- 34922602
- Doi
- 10.1186/s13058-021-01488-7
- Paper Title
- Triptonide effectively inhibits triple-negative breast cancer metastasis through concurrent degradation of Twist1 and Notch1 oncoproteins
- Paper 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-kappaB 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-kappaB 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.
- Journal
- Breast Cancer Res
- Publish Year
- 2021
- Experiment Subject
- mouse; tnbc cells
- Experiment Type
- Animal Experiment
- Phenotype Related
- Triple-negative Breast Cancer; Tumor; Tnbc Tumor
- Paper Title Cn
- Paper Title En
- Triptonide effectively inhibits triple-negative breast cancer metastasis through concurrent degradation of Twist1 and Notch1 oncoproteins
- Bilingual Status
- semi_complete