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Carcinogenesis Advance Access originally published online on November 20, 2006
Carcinogenesis 2007 28(5):977-987; doi:10.1093/carcin/bgl221
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Silibinin suppresses human osteosarcoma MG-63 cell invasion by inhibiting the ERK-dependent c-Jun/AP-1 induction of MMP-2

Yih-Shou Hsieh1, Shu-Chen Chu2, Shun-Fa Yang3, Pei-Ni Chen1, Yu-Chuan Liu1 and Ko-Hsiu Lu3,4,*

1 Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan
2 Department of Food Science, Central Taiwan University of Science and Technology, Taichung, Taiwan
3 Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
4 Department of Orthopaedic Surgery, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 402, Taiwan

* To whom correspondence should be addressed. Tel: +886 4 24739595; Fax: +886 4 24756437; Email: cshy307{at}csh.org.tw

Silibinin is a natural flavonoid antioxidant with anti-hepatotoxic properties and pleiotropic anticancer capabilities. We tested the hypothesis that silibinin inhibits cellular invasiveness by down-regulating the focal adhesion kinase (FAK) and extracellular signal-regulated protein kinase (ERK)-dependent c-Jun/activator protein-1 (AP-1) induction, which leads to inhibition of urokinase-type plasminogen activator (u-PA) and matrix metalloproteinase-2 (MMP-2) expressions in human osteosarcoma MG-63 cells. We found that silibinin decreased cell adhesion and invasiveness, as well as inhibited u-PA and MMP-2 expressions. Silibinin reduced ERK 1/2 phosphorylation, but had no effects on the phosphorylation of c-Jun N-terminal kinases (JNKs) 1/2, p38 and Akt. Silibinin suppressed AP-1-binding activity and c-Jun levels and its phosphorylation without changes of c-Fos and Ets-1 levels. Silibinin also inhibited interleukin-6-induced ERK 1/2 and c-Jun phosphorylation, and cell invasiveness. Thus, silibinin may possess an anti-metastatic activity in MG-63 cells.

Abbreviations: AP-1, activator protein-1; cDNA, complementary DNA; ECM, extracellular matrix; ERK, extracellular signal-regulated protein kinase; FAK, focal adhesion kinase; IL, interleukin; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEM, minimum essential medium; MMP, matrix metalloproteinase; MEK, mitogen-activated protein kinase kinase; NF-{kappa}B, nuclear factor-{kappa}B; PAI, plasminogen activator inhibitor; PBS, phosphate-buffered saline; PI3K, phosphatidylinositol 3-kinase; PCR, polymerase chain reaction; TIMP, tissue inhibitor of metalloproteinase; u-PA, urokinase-type plasminogen activator

Received January 18, 2006; revised November 2, 2006; accepted November 6, 2006.


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