ポスターセッション

一覧　トップ

ビタミンK誘導体による培養肝癌細胞増殖抑制機構: アリル化によるチロシン脱リン酸化酵素阻害作用の意義: 西川祐司（Thomas E. Starzl 移植研究所, ピッツバーグ大）

Inhibition of hepatoma cell growth in vitro by arylating and non-arylating vitamin K analogs: significance of protein tyrosine phosphatase inhibition: Yuji NISHIKAWA (Thomas E. Starzl Transplantation Institute, University of Pittsburgh)

We previously reported that vitamin K analogs with a thioether side chain strongly inhibited cell growth and suggested that the action was mainly due to sulfhydryl arylation of cellular thiols. Recently, we found that a thioether analog (Cpd 5) inhibited the activity of protein tyrosine phosphoatases (PTPases), which have a critical cysteine in their active site, and induced protein tyrosine phosphorylation, but not serine or threonine phosphorylation, in a human hepatoma cell line (Hep3B). In this study, we examined structural requirements for induction of protein tyrosine phosphorylation in Hep3B cells and inhibition of PTPase by several vitamin K analogs. Thioether analogs (arylators), especially those with a hydroxy (Cpd 5) or a methoxy (Cpd 38) growp at the end of side chain, induced protein tyrosine phosphorylation and inhibited the activity of purified PTPase, but non-arylating analogs did not. Among the receptor tyrosine kinases, EGF receptor was tyrosine-phosphorylated by the treatment with thioether analogs, while insulin and HGF receptors were not. An increase in tyrosine phosphorylated ERK2 MAP kinase was also observed. Analogs with stronger effects on protein tyrosine phosphorylation and PTPase inhibition were also more potent growth inhibitors. These results suggest that cell growth inhibition by thioether analogs is closely associated with inhibition of PTPases by sulfhydryl arylation and specific tyrosine phosphorylation of selected proteins.
This work has been done under the guidance of Dr. B. I. Carr (Transpl. Institute) with collaboration with Drs. J. Kerns and C. S. Wilcox (Dept. of Chemistry, University of Pittsburgh)