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

Abstract

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 K 2 in HCC cells in vitro and in vivo. H epatocellular carcinoma (HCC) is one of the major malignancies in the world. 1 Recent progress in treatment modalities has improved the prognosis of patients with HCC. 2-4 However, the long-term prognosis remains disappointing because of the frequent recurrence of HCC 5 and the development of portal venous invasion (PVI) of HCC in 16%-65% of patients, 6,7 resulting in the extensive spread of tumor cells throughout the liver. 8 Prior to this study, we and others observed PVI more frequently in HCC patients with positive des-gammacarboxy prothrombin (DCP), a serum protein induced by the absence of vitamin K, than in patients with negative DCP. 9 Moreover, serum DCP levels at the time of the HCC diagnosis were found in a prospective study to be the most significant predisposing factor for the development of PVI. 9 Prothrombin is a vitamin K-dependent plasma coagulation factor that is synthesized in the liver. The precursor of prothrombin contains 10 glutamic acid residues in its amino-terminal domain. These residues must undergo complete carboxylation to ␥-carboxyglutamic acid in the presence of vitamin K for prothrombin to display coagulation activity. DCP is an abnormal prothrombin that is not completely carboxylated. Although the precise causes of DCP production are unknown, 10 the concentration of vitamin K is normal in nontumorous parts of the liver but is decreased significantly in HCC tissues. 11 Vitamin K is a fat-soluble essential vitamin; its only known physiological role is as a cofactor for ␥-glutamylcarboxylase, which acts on several blood-clotting pro-

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

“…The safety, relatively low cost, and ease of use make vitamin K 2 a suitable candidate for clinical trials that assess the value of combination of chemoprevention or chemotherapy in at-risk patients or in patients with a confirmed diagnosis of HCC [116,[122][123][124][125].…”

“…Otsuka et al [123] examined the biological effects of extrinsic supplementation of vitamin K 2 in HCC cells in vitro and in vivo. Administration of vitamin K 2 to nude mice inoculated with liver tumor cells reduced both tumor growth and weight loss.…”

Vitamin K2 augments 5-fluorouracil-induced growth inhibition of human hepatocellular carcinoma cells by inhibiting NF-κB activation

“…VK2 has been reported to show anticancer effects inducing apoptosis and cell cycle arrest in several tumor cell types such as leukemia cells, osteosarcoma cells, HCC cells, glioma cells, and lung cancer cells, also a number of striking anecdotal clinical reports supports use of VK2 as an anticancer agent (7)(8)(9)(10)(11)(12)(13)22). However, therapies combining VK2 with established anti-tumor agents have not been investigated.…”

“…Cell cycle arrest and apoptosis are believed to be involved in this action of VK2, but precise molecular mechanisms underlying VK2-induced growth inhibition and killing in HCC cells remain to be elucidated. Recently VK2 also was found to inhibit hepatoma cell invasiveness and metastasis (11). More importantly, we recently demonstrated that administration of VK2 to HCC patients significantly decreased recurrence of HCC after curative local ablation therapy (12).…”

Growth inhibitory actions of prothrombin on normal hepatocytes: Influence of matrix

“…The biological significance of this has never been clear, but it has recently been suggested that immature prothrombin or DCP has HCC growth promoting properties (Suzuki et al, 2005). This led us to consider that mature prothrombin, a major vitamin K-dependent blood coagulation factor, might also have growth regulatory properties, since K vitamins have previously been shown to have growth inhibitory activities (Yoshida etal., 2003;Otsuka et al, 2004;Lamson and Plaza, 2003;Wang et al, 1995;Nishikawa et al, 1995;Hitomi et al, 2005;Bouzahzah et al, 1995) in addition to their well-described physiological effects as cofactors for several blood coagulation proteins (such as prothrombin and factors VII, IX and X).…”