Vitamin K₂ inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation

Hepatocellular carcinoma (HCC) is a common human malignancy. Its high mortality rate is mainly a result of high intrahepatic recurrence and portal venous invasion (PVI). We previously reported that the development of PVI is related to levels of des-gamma-carboxy prothrombin (DCP), a serum protein that increases at a notably higher rate in patients with HCC. Because DCP is produced by a vitamin K shortage, we examined the biological effects of extrinsic supplementation of vitamin K₂ in HCC cells in vitro and in vivo. Consequently, vitamin K₂ inhibits the growth and invasion of HCC cells through the activation of protein kinase A, which modulates the activities of several transcriptional factors and inhibits the small GTPase Rho, independent of suppression of DCP. In addition, administration of vitamin K ₂ to nude mice inoculated with liver tumor cells reduced both tumor growth and body weight loss. In conclusion, similar to an acyclic retinoid-which was previously reported to prevent the recurrence of HCC-vitamin K₂, another lipid-soluble vitamin, may be a promising therapeutic means for the management of HCC.