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

• Published in: Journal of agricultural and food chemistry Vol. 58; no. 17; pp. 9468 - 9475
• Main Authors: Huang, Guan-Jhong, Yang, Chih-Min, Chang, Yuan-Shiun, Amagaya, Sakae, Wang, Hsiao-Chieh, Hou, Wen-Chi, Huang, Shyh-Shyun, Hu, Miao-Lin
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 08.09.2010
• Subjects: anticarcinogenic activity; Bioactive Constituents; biochemical pathways; Biological and medical sciences; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Catechols - pharmacology; Cell Adhesion; cell culture; Cell Line, Tumor; Cell Movement; disease control; enzyme inhibition; enzyme inhibitors; Food industries; functional foods; Fundamental and applied biological sciences. Psychology; Hispolon; human cell lines; Humans; liver neoplasms; Liver Neoplasms - enzymology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Magnetic Resonance Spectroscopy; Matrix Metalloproteinase Inhibitors; matrix metalloproteinase-2/9; metalloproteinases; metastasis; Neoplasm Metastasis - prevention & control; Phellinus; Phellinus linteus; Protein Kinases - drug effects; signal transduction; Signal Transduction - drug effects; SK-Hep1 human hepatoma cell; u-plasminogen activator; Urokinase-Type Plasminogen Activator - antagonists & inhibitors; Phellinus linteus; Hispolon; MMP-2; MMP-9; uPA; Human; Activator; Plasminogen; Cell
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/jf101508r

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.