Abstract
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.
Highlights
Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) and is highly metastatic and lethal [1, 2]
Triptonide triggers the degradation of oncoproteins Twist1 and Notch1 in TNBC cells
Triptonide markedly reduced the colony numbers of highly metastatic MDA-MB-231 (Fig. 1C, D) and MDA-MB-468 cells (Fig. 1E, F) in a concentration-dependent manner, suggesting that triptonide is a potent inhibitor of TNBC cell tumorigenesis
Summary
Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) and is highly metastatic and lethal [1, 2]. Substantial efforts have gone into identifying treatments for TNBC in recent decades, the median survival time of TNBC patients is still less than 15 months largely due to the absence of effective drugs in the clinic [3, 4]. It was recently reported that 411 genes were overexpressed in TNBC tumor tissue compared to normal breast tissue and that multiple tumorigenic and metastatic signaling pathways were aberrantly activated [6, 7]. 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
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