Timosaponin AIII Suppresses Hepatocyte Growth Factor-Induced Invasive Activity through Sustained ERK Activation in Breast Cancer MDA-MB-231 Cells

Abstract EN

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.