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 K(2) in HCC cells in vitro and in vivo. Consequently, vitamin K(2) 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 K(2), another lipid-soluble vitamin, may be a promising therapeutic means for the management of HCC.
Otsuka
Motoyuki
M
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Kato
Naoya
N
Shao
Run-Xuan
RX
Hoshida
Yujin
Y
Ijichi
Hideaki
H
Koike
Yukihiro
Y
Taniguchi
Hiroyoshi
H
Moriyama
Masaru
M
Shiratori
Yasushi
Y
Kawabe
Takao
T
Omata
Masao
M
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D015398:Signal Transduction / Q000187:drug effects; D024482:Vitamin K 2 / Q000494:pharmacology*; D020687:cdc25 Phosphatases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors
D024482:Vitamin K 2; D017868:Cyclic AMP-Dependent Protein Kinases; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases; D020742:rhoA GTP-Binding Protein