Abstract
Background. The aim of this study was to investigate the mechanisms by which Timosaponin AIII (TAIII) is able to inhibit HGF-induced invasion activity in the triple negative breast cancer cell line MDA-MB-231. Methods. After pretreatment with different concentrations (10−6~10−8 M) of TAIII, the cells were treated with hepatocyte growth factor (HGF, 15 ng/mL). At different time intervals after coincubation, various parameters, including the expression of c-Met, ERK, COX2, and MMP-9, which were assessed by Western blotting or by real-time PCR, were analyzed. In addition, invasive activity was also monitored. Results. HGF was found to induce c-MET activation and ERK activation, together with increased COX2 protein expression; these changes were followed by a subsequent increase in invasive activity. TAIII was found to suppress HGF-induced invasive activity and COX2 gene expression in a concentration-dependent manner (10−6~10−8 M) in parallel with increases in the phosphoforms of c-Met and ERK after TAIII treatment. The mechanisms by which TAIII suppresses HGF-induced invasive activity were demonstrated to include sustained cytoplasmic and nuclear ERK activation; these led to a suppression of nuclear ATF2 activation, which was followed by downregulation of COX2 and MMP-9 transcription. Conclusion. TAIII suppresses HGF-induced invasive activity in MDA-MB-231 cells via sustained ERK activation.
Highlights
Breast cancer is the most common invasive female cancer worldwide, and this is true for Taiwan [1]
We demonstrate that Timosaponin AIII (TAIII) suppresses the hepatocyte growth factor (HGF)-induced invasive activity of MDA-MB-231 cells via sustained extracellular signal-regulated kinase 1/2 (ERK) activation and that this subsequently suppresses nuclear Activating transcription factor 2 (ATF2) expression, which results in a downregulation of COX gene expression
In order to elucidate the role of COX2 protein in the TAIII suppression of HGF-induced invasive activity, cultured cells were cotreated with TAIII and HGF, and this was followed by Western blot analysis and real-time PCR to assess COX2 gene expression
Summary
Breast cancer is the most common invasive female cancer worldwide, and this is true for Taiwan [1]. Triplenegative breast cancers (TNBC), a subtype of breast cancer that is characterized by absence of estrogen receptors (ER), progesterone receptors (PR), and a lack of overexpression of human epidermal growth factor receptor 2 (HER2), account for about 15% of all breast cancer cases [2] These tumors characteristically occur in younger women. An increasing range of biomarkers associated with various subtypes of breast cancer has been identified [3] Some of these biomarkers are involved in tumor-cell proliferation, survival, and invasiveness, and these may provide a rational basis for the development of molecularly targeted therapies that can treat malignancies such as TNBC. TAIII suppresses HGF-induced invasive activity in MDA-MB-231 cells via sustained ERK activation
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