Abstract
Breast cancer (BC) a very common cancer in women worldwide. Triple negative breast cancer (TNBC) has been shown to have a poor prognosis with a high level of tumor metastatic spread. Here, the inhibitory effects of ginsenoside-Rh1 (Rh1) on BC metastasis, and its underlying signaling pathway in TNBC were investigated. Rh1-treated MDA-MB-231 cells were analyzed for metastasis using a wound healing assay, transwell migration and invasion assay, western blotting, and qRT-PCR. Rh1 treatment significantly inhibited BC metastasis by inhibiting the both protein and mRNA levels of MMP2, MMP9, and VEGF-A. Further, Rh1-mediated inhibitory effect on BC migration was associated with mitochondrial ROS generation. Rh1 treatment significantly eliminated STAT3 phosphorylation and NF-κB transactivation to downregulate metastatic factors, such as MMP2, MMP9, and VEGF-A. In addition, Mito-TEMPO treatment reversed Rh1 effects on the activation of STAT3, NF-κB, and their transcriptional targets. Rh1 further enhanced the inhibitory effects of STAT3 or NF-κB specific inhibitor, stattic or BAY 11-7082 on MMP2, MMP9, and VEGF-A expression, respectively. In summary, our results revealed the potent anticancer effect of Rh1 on TNBC migration and invasion through mtROS-mediated inhibition of STAT3 and NF-κB signaling.
Highlights
Thereafter, we investigated the inhibitory effects of Rh1 on the migration and invasion of MDA-MB-231 cells
Rh1 treatment significantly decreased wound healing ability in a dose-dependent manner in MDA-MB-231 cells (Figure 1g,h). These results indicate that Rh1 has a superior ability to regulate cancer cell wound healing, migration, and invasion in MDA-MB-231 cells
BCpatients patientshave haveincreased increased with develAlthough with thethe developopment of therapeutic strategies, metastasis is the most common cause of cancer death ment of Breast cancer (BC) therapeutic strategies, metastasis is the most common cause of cancer death in in approximately
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Previous reports demonstrated that ROS can regulate cancer proliferation and apoptosis by ROS-mediated kinase activation, and its effects were inhibited by ROS scavengers, such as N-acetyl-cysteine (NAC) [8,9]. Several studies have demonstrated that STAT3 plays a crucial role in BC proliferation and metastasis by inducing MMP family proteins such as MMP2, 7, 9, and 13 or vascular endothelial growth factor (VEGF) expression through gene regulation [9,14,15]. Several studies have indicated that Rh1 inhibits cancer proliferation, migration, and invasion by regulating of MAPK or PI3K/Akt-mediated MMP1, 3, and 9 expressions in colorectal cancer, hepatocellular carcinoma, and astroglioma cells [22,23,24]. Rh1 treatment significantly induced mitochondrial dysfunction-mediated ROS production, leading to the inhibition of the STAT/NF-κB signaling pathway in MDA-MB-231 cells
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