menatetrenone and Cell-Transformation--Neoplastic

Vitamin K is a cofactor for γ-glutamyl carboxylase, which catalyzes the posttranslational conversion of specific glutamyl residues to γ-carboxyglutamyl residues in a variety of vitamin K-dependent proteins (VKDPs) involved in blood coagulation, bone and cartilage metabolism, signal transduction, and cell proliferation. Despite the great advances in the genetic, structural, and functional studies of VKDPs as well as the enzymes identified as part of the vitamin K cycle which enable it to be repeatedly recycled within the cells, little is known of the identity and roles of key regulators of vitamin K metabolism in mammals and humans. This review focuses on new insights into the molecular mechanisms underlying the intestinal absorption and in vivo tissue conversion of vitamin K1 to menaquinone-4 (MK-4) with special emphasis on two major advances in the studies of intestinal vitamin K transporters in enterocytes and a tissue MK-4 biosynthetic enzyme UbiA prenyltransferase domain-containing protein 1 (UBIAD1), which participates in the in vivo conversion of a fraction of dietary vitamin K1 to MK-4 in mammals and humans, although it remains uncertain whether UBIAD1 functions as a key regulator of intracellular cholesterol metabolism, bladder and prostate tumor cell progression, vascular integrity, and protection from oxidative stress.

Topics: Animals; Cell Transformation, Neoplastic; Cholesterol; Dimethylallyltranstransferase; Enterocytes; Humans; Intestinal Absorption; Mice; Neoplasms; Oxidative Stress; Vitamin K; Vitamin K 2

We examined whether phosphatidylcholine inhibited growth of hepatic cancer, as previously shown for menaquinone-4 (vitamin K2).. Growth inhibitions by phosphatidylcholine and/or menaquinone-4 and apoptosis induction by phosphatidylcholine were evaluated in vitro using human hepatic cancer cell lines (Hep-3B, Hep-G2, HuH-7, and Alexander). Effects of these agents were then investigated in male Sprague-Dawley rats against hepatocarcinogenesis induced by diethylnitrosamine plus phenobarbital. All rats were killed to examine livers to evaluate inhibitory potential macroscopically and immunohistochemically using an antibody against the marker of carcinogenesis, glutathione S-transferase and apoptotic induction by phosphatidylcholine using TUNEL staining. Blood samples were obtained by cardiac puncture.. In vitro, phosphatidylcholine and menaquinone-4 each inhibited cancer cell growth and phosphatidylcholine induced apoptosis dose-dependently. Moreover, exposure to both synergistically inhibited growth in Hep-3B. In vivo, diets containing phosphatidylcholine with or without menaquinone-4 significantly reduced the number of macroscopic hepatic tumor nodules and the extent of abnormally immunoreactive foci conserving hepatic function on serum examinations compared with controls given only the carcinogens. Moreover, phosphatidylcholine supplementation induced apoptosis on TUNEL staining of liver sections.. Given together, phosphatidylcholine and menaquinone-4 may exhibit synergy against hepatocarcinogenesis conserving hepatic function that could benefit patients at high risk for hepatocellular carcinoma.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Diet; Diethylnitrosamine; Drug Synergism; Humans; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Phenobarbital; Phosphatidylcholines; Rats; Rats, Sprague-Dawley; Vitamin K 2