Hispolon suppresses SK-Hep1 human hepatoma cell metastasis by inhibiting matrix metalloproteinase-2/9 and urokinase-plasminogen activator through the PI3K/Akt and ERK signaling pathways.
Cancer metastasis is a primary cause of cancer death. Hispolon is an active phenolic compound of Phellinus linteus, a mushroom that has recently been shown to have antioxidant and anticancer activities. In this study, we first observed that hispolon exerted a dose-dependent inhibitory effect on invasion and motility, but not on adhesion, of the highly metastatic SK-Hep1 cells in the absence of cytotoxicity. Mechanistically, hispolon decreased the expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-plasminogen activator (uPA) in a concentration-dependent manner. Hispolon also inhibited phosphorylation of extracellular signaling-regulating kinase1/2 (ERK1/2), phosphatidylinositol-3-kinase/serine/threonine protein kinase (or protein kinase B (PI3K/Akt), and focal adhesion kinase (FAK). Furthermore, treatment of SK-Hep1 cells with an inhibitor specific for ERK1/2 (PD98256) decreased the expression of MMP-2, and MMP-9. These results demonstrate that hispolon can inhibit the metastasis of SK-Hep1 cells by reduced expression of MMP-2, MMP-9, and uPA through the suppression of the FAK signaling pathway and of the activity of PI3K/Akt and Ras homologue gene family, member A (RhoA). These findings suggest that hispolon may be used as an antimetastatic agent.
Huang
Guan-Jhong
GJ
Institute of Chinese Pharmaceutical Sciences, College of Pharmacy, China Medical University, 91 Hsueh-Shih Road, Taichung City 404, Taiwan. gjhuang@mail.cmu.edu.tw
Yang
Chih-Min
CM
Chang
Yuan-Shiun
YS
Amagaya
Sakae
S
Wang
Hsiao-Chieh
HC
Hou
Wen-Chi
WC
Huang
Shyh-Shyun
SS
Hu
Miao-Lin
ML
D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002396:Catechols / Q000494:pharmacology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy; D061965:Matrix Metalloproteinase Inhibitors; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D011494:Protein Kinases / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*
D002396:Catechols; D061965:Matrix Metalloproteinase Inhibitors; C103442:hispolon; D011494:Protein Kinases; D014568:Urokinase-Type Plasminogen Activator