Suppression of metastasis of intravenously-inoculated B16/F10 melanoma cells by the novel ginseng-derived ingredient, gintonin: Involvement of autotaxin inhibition

Abstract

Ginseng has been used for cancer prevention. However, little is known about its active components and the molecular mechanisms underlying its effects. Recently, we isolated a unique lysophosphatidic acid (LPA) receptor ligand, gintonin. Gintonin contains approximately 9.5% LPA, mainly LPA C18:2. Autotaxin (ATX) is responsible for metastasis by overproducing LPA in cancers. However, LPA, particularly LPA C18:2, is a strong negative feedback ATX inhibitor. It is unknown whether gintonin inhibits ATX activity and whether gintonin-induced ATX inhibition is coupled with antimetastatic activity. In this study, we examined whether gintonin and LPA C18:2 inhibit ATX activity and metastasis-related cellular activities in melanoma cells. We found that gintonin and LPA C18:2 inhibited the purified and secreted ATX activity from melanoma cells in a concentration-dependent manner. Gintonin also inhibited cell migration with a minimal inhibition of cell growth. The oral administration of gintonin or LPA C18:2 inhibited lung metastasis induced by tail-vein inoculations of melanoma cells. Moreover, the oral administration of gintonin significantly suppressed the tumor growth induced by subcutaneous grafts of melanoma cells. A histological analysis showed that the oral administration of gintonin reduced tumor necrosis, the pleomorphism of tumor cells, tumor cell mitosis and angiogenesis. The present study demonstrates that the gintonin-induced inhibition of ATX activity may be the molecular basis of ginseng-induced antimetastatic and antitumor activities.