title: Timosaponin AIII Suppresses Hepatocyte Growth Factor-Induced Invasive Activity through Sustained ERK Activation in Breast Cancer MDA-MB-231 Cells.
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.
authors.affiliation: Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, No. 155, Section 2, Linong Street, Beitou, Taipei 112, Taiwan ; Division of General Surgery, Department of Surgery, Mackay Memorial Hospital, No. 92, Section 2, Zhongshan N. Road, Taipei 10449, Taiwan.
authors.forename: Chung-Hsin
authors.initials: CH
authors.lastname: Tsai
authors.forename: Chu-Wen
authors.initials: CW
authors.lastname: Yang
authors.forename: Jir-You
authors.initials: JY
authors.lastname: Wang
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Tsai
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.forename: Kuan-Liang
authors.initials: KL
authors.lastname: King
authors.forename: Wei-Shone
authors.initials: WS
authors.lastname: Chen
authors.forename: Jen-Hwey
authors.initials: JH
authors.lastname: Chiu
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Shyr