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

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.