Silibinin prevents TPA-induced MMP-9 expression and VEGF secretion by inactivation of the Raf/MEK/ERK pathway in MCF-7 human breast cancer cells

• Published in: Phytomedicine (Stuttgart) Vol. 16; no. 6; pp. 573 - 580
• Main Authors: Kim, Sangmin, Choi, Jae Hyuck, Lim, Hye In, Lee, Se-Kyung, Kim, Wan Wook, Kim, Jee Soo, Kim, Jung-Han, Choe, Jun-Ho, Yang, Jung-Hyun, Nam, Seok Jin, Lee, Jeong Eon
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.06.2009
• Subjects: 12-O-tetradecanoyl phorbol-13-acetate (TPA); Blotting, Western; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Enzyme-Linked Immunosorbent Assay; Humans; MAP Kinase Signaling System; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinase-9 (MMP-9); MCF-7 human breast cancer cells; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Silibinin; Silybum marianum; Silymarin - pharmacology; Tetradecanoylphorbol Acetate - pharmacology; Vascular endothelial growth factor (VEGF); Vascular Endothelial Growth Factor A - secretion; MCF-7 human breast cancer cells; 12-O-tetradecanoyl phorbol-13-acetate (TPA); Matrix metalloproteinase-9 (MMP-9); Silybum marianum; Silibinin; Vascular endothelial growth factor (VEGF)
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2008.11.006

Matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression are pivotal steps in cancer metastasis. Herein, we investigated the effect of silibinin, a major constituent (flavanolignan) of the fruits of Silybum marianum, on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 and VEGF expression in MCF-7 human breast cancer cells. The expression of MMP-9 and VEGF in response to TPA was increased, whereas TPA-induced MMP-9 and VEGF expression was decreased by silibinin. To investigate the regulatory mechanism of silibinin on TPA-induced MMP-9 and VEGF expression, we pretreated cells with various inhibitors, such as UO126 (MEK1/2 inhibitor), SP600125 (JNK inhibitor), and SB203580 (p38 inhibitor). Interestingly, TPA-induced MMP-9 expression was significantly inhibited by UO126, but not by SP600125 and SB203580. In addition, we pretreated cells with 100 μM silibinin prior to TPA treatment. TPA-induced MEK and ERK phosphorylation was significantly decreased by silibinin in MCF7 cells. TPA-induced VEGF expression was also suppressed by UO126. On the other hand, we found that adenoviral constitutive active-MEK (Ad-CA-MEK) significantly increased MMP-9 and VEGF expression. Taken together, we suggest that the inhibition of TPA-induced MMP-9 and VEGF expression by silibinin is mediated by the suppression of the Raf/MEK/ERK pathway in MCF-7 breast cancer cells.