Xiao H, Nagai Y, Fukui Y, Tamiyakoizumi K, Iwata H, Watanabe T, Hamaguchi M
NAGOYA UNIV,SCH MED,DIS MECHANISM & CONTROL RES INST,SHOWA KU,NAGOYA,AICHI 466,JAPAN. UNIV TOKYO,INST MED SCI,MINATO KU,TOKYO 108,JAPAN. UNIV TOKYO,FAC AGR,BIOCHEM LAB,BUNKYO KU,TOKYO 113,JAPAN. FUJITA HLTH UNIV,SCH MED,HISAI 4241,JAPAN.
Int J Oncol. 1995 Feb;6(2):405-11. doi: 10.3892/ijo.6.2.405.
To reveal the signaling pathway leading to oncogenecity of human cancer cells, we examined the expression and tyrosine-phosphorylation of phosphatidylinositol (PI)-3 kinase in cancer cell lines. Of the 14 cell lines examined, two poorly differentiated human gastric cancer cell lines, NUGC-4 and MKN-45, which were previously found to have aberrant elevation of tyrosine phosphorylation showed elevated levels of PI-3 kinase 85-kDa subunit expression. In these cells, tyrosine-phosphorylation and overall activity of PI-3 kinase were apparently elevated, compared with normal human fibroblasts and another well differentiated gastric cancer cell line, MKN-28. Treatment of these cells with tyrosine kinase inhibitor, genistein, strongly suppressed the PI-3 kinase activity. Furthermore, wortmannin, a potent inhibitor of PI-3 kinase, strongly suppressed the growth of these gastric cancer cells. These results suggest that the growth signaling via tyrosine phosphorylation is required for the activation of PI-3 kinase in NUGC4 and MKN-45, and that this activation plays an important role in oncogenic growth of these cells. However, these two cell lines showed different responses of PI-3 kinase to acid-treatment and tyrosine kinase inhibitors. In MKN-45, activation of PI-3 kinase appeared to be constitutive, and could be relevant to the oncogenic nature of the cell line.
为了揭示导致人类癌细胞致癌性的信号通路，我们检测了癌细胞系中磷脂酰肌醇（PI）-3激酶的表达及酪氨酸磷酸化情况。在所检测的14个细胞系中，之前发现酪氨酸磷酸化异常升高的两个低分化人胃癌细胞系NUGC-4和MKN-45，其PI-3激酶85-kDa亚基的表达水平升高。与正常人成纤维细胞和另一个高分化胃癌细胞系MKN-28相比，在这些细胞中，PI-3激酶的酪氨酸磷酸化和总体活性明显升高。用酪氨酸激酶抑制剂染料木黄酮处理这些细胞，可强烈抑制PI-3激酶的活性。此外，PI-3激酶的强效抑制剂渥曼青霉素可强烈抑制这些胃癌细胞的生长。这些结果表明，在NUGC4和MKN-45中，PI-3激酶的激活需要通过酪氨酸磷酸化的生长信号，并且这种激活在这些细胞的致癌性生长中起重要作用。然而，这两个细胞系对酸处理和酪氨酸激酶抑制剂显示出不同的PI-3激酶反应。在MKN-45中，PI-3激酶的激活似乎是组成性的，可能与该细胞系的致癌特性有关。
