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Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation.
Clin Cancer Res. 2007 Apr 01; 13(7):2236-45.CC

Abstract

PURPOSE

Menatetrenone, a vitamin K2 analogue, plays an important role in the production of blood coagulation factors. Menatetrenone has also bee shown to have antineoplastic effects against several cancer cell lines including hepatocellular carcinoma (HCC) cells. However, the mechanisms by which vitamin K2 inhibits HCC cell growth have not bee fully clarified, and we therefore investigated the molecular basis of vitamin K2-induced growth inhibition of HCC cells.

EXPERIMENTAL DESIGN

HCC cells were treated with vitamin K2 and the expression of several growth-related genes including cyclin-dependent kinase inhibitors and cyclin D1 was examined at the mRNA and protein levels. A reporter gene assay of the cyclin D1 promoter was done under vitamin K2 treatment. The regulation of nuclear factor kappaB (NF-kappaB) activation was investigated by a NF-kappaB reporter gene assay, an electrophoretic mobility shift assay, a Western blot for phosphorylated IkappaB, and an in vitro kinase assay for IkappaB kinase (IKK). We also examined the effect of vitamin K2 on the growth of HCC cells transfected with p65 or cyclin D1.

RESULTS

Vitamin K2 inhibited cyclin D1 mRNA and protein expression in a dose-dependent manner in the HCC cells. Vitamin K2 also suppressed the NF-kappaB binding site-dependent cyclin D1 promoter activity and suppressed the basal, 12-O-tetradecanoylphorbol-13-acetate (TPA)-, TNF-alpha-, and interleukin (IL)-1-induced activation of NF-kappaB binding and transactivation. Concomitant with the suppression of NF-kappaB activation, vitamin K2 also inhibited the phosphorylation and degradation of IkappaBalpha and suppressed IKK kinase activity. Moreover, HCC cells overexpressing cyclin D1 and p65 became resistant to vitamin K2 treatment.

CONCLUSION

Vitamin K2 inhibits the growth of HCC cells via suppression of cyclin D1 expression through the IKK/IkappaB/NF-kappaB pathway and might therefore be useful for treatment of HCC.

Authors+Show Affiliations

Division of Hepatology and Metabolism, Department of Internal Medicine, and Health Administration Center, Saga Medical School, Saga University, Nabeshima, Saga, Japan. ozaki@cc.saga-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17404108

Citation

Ozaki, Iwata, et al. "Menatetrenone, a Vitamin K2 Analogue, Inhibits Hepatocellular Carcinoma Cell Growth By Suppressing Cyclin D1 Expression Through Inhibition of Nuclear Factor kappaB Activation." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 13, no. 7, 2007, pp. 2236-45.
Ozaki I, Zhang H, Mizuta T, et al. Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation. Clin Cancer Res. 2007;13(7):2236-45.
Ozaki, I., Zhang, H., Mizuta, T., Ide, Y., Eguchi, Y., Yasutake, T., Sakamaki, T., Pestell, R. G., & Yamamoto, K. (2007). Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 13(7), 2236-45.
Ozaki I, et al. Menatetrenone, a Vitamin K2 Analogue, Inhibits Hepatocellular Carcinoma Cell Growth By Suppressing Cyclin D1 Expression Through Inhibition of Nuclear Factor kappaB Activation. Clin Cancer Res. 2007 Apr 1;13(7):2236-45. PubMed PMID: 17404108.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation. AU - Ozaki,Iwata, AU - Zhang,Hao, AU - Mizuta,Toshihiko, AU - Ide,Yasushi, AU - Eguchi,Yuichiro, AU - Yasutake,Tsutomu, AU - Sakamaki,Toshiyuki, AU - Pestell,Richard G, AU - Yamamoto,Kyosuke, PY - 2007/4/4/pubmed PY - 2007/6/22/medline PY - 2007/4/4/entrez SP - 2236 EP - 45 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 13 IS - 7 N2 - PURPOSE: Menatetrenone, a vitamin K2 analogue, plays an important role in the production of blood coagulation factors. Menatetrenone has also bee shown to have antineoplastic effects against several cancer cell lines including hepatocellular carcinoma (HCC) cells. However, the mechanisms by which vitamin K2 inhibits HCC cell growth have not bee fully clarified, and we therefore investigated the molecular basis of vitamin K2-induced growth inhibition of HCC cells. EXPERIMENTAL DESIGN: HCC cells were treated with vitamin K2 and the expression of several growth-related genes including cyclin-dependent kinase inhibitors and cyclin D1 was examined at the mRNA and protein levels. A reporter gene assay of the cyclin D1 promoter was done under vitamin K2 treatment. The regulation of nuclear factor kappaB (NF-kappaB) activation was investigated by a NF-kappaB reporter gene assay, an electrophoretic mobility shift assay, a Western blot for phosphorylated IkappaB, and an in vitro kinase assay for IkappaB kinase (IKK). We also examined the effect of vitamin K2 on the growth of HCC cells transfected with p65 or cyclin D1. RESULTS: Vitamin K2 inhibited cyclin D1 mRNA and protein expression in a dose-dependent manner in the HCC cells. Vitamin K2 also suppressed the NF-kappaB binding site-dependent cyclin D1 promoter activity and suppressed the basal, 12-O-tetradecanoylphorbol-13-acetate (TPA)-, TNF-alpha-, and interleukin (IL)-1-induced activation of NF-kappaB binding and transactivation. Concomitant with the suppression of NF-kappaB activation, vitamin K2 also inhibited the phosphorylation and degradation of IkappaBalpha and suppressed IKK kinase activity. Moreover, HCC cells overexpressing cyclin D1 and p65 became resistant to vitamin K2 treatment. CONCLUSION: Vitamin K2 inhibits the growth of HCC cells via suppression of cyclin D1 expression through the IKK/IkappaB/NF-kappaB pathway and might therefore be useful for treatment of HCC. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/17404108/Menatetrenone_a_vitamin_K2_analogue_inhibits_hepatocellular_carcinoma_cell_growth_by_suppressing_cyclin_D1_expression_through_inhibition_of_nuclear_factor_kappaB_activation_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17404108 DB - PRIME DP - Unbound Medicine ER -