Jiang Tiejun, Zhu Yongliang, Luo Cong, Lu Xiaoyong, Zhang Wo, Qiu Fuming, Huang Jian
Cancer Institute, Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.
Planta Med. 2007 Sep;73(11):1176-81. doi: 10.1055/s-2007-981592. Epub 2007 Sep 7.
Matrine, from Sophora flavescens, could remarkably inhibit tumor growth and induce apoptosis in various cancer cells in vitro. eIF4E and its inhibitor 4E-BP1 play key roles in regulating mRNA translation and cell proliferation. However, it remained elusive whether matrine inhibited cancer cells growth through attenuating the activity of 4E-BP1. In this study, we analyzed the effects of matrine on 4E-BP1 and eIF4E in gastric cancer MKN45 cells. Immunoblots showed that matrine inhibited the activity of eIF4E through dephosphorylation of 4E-BP1 in a dose- and time-dependent manner. We found that matrine inactivated Erk1/2, an upstream regulator of 4E-BP1 and eIF4E, and remarkably reduced the phosphorylation level of 4E-BP1 and eIF4E, whereas 4E-BP1 was little influenced by JNK, p38 or Akt/mTOR. Inactivation of PP2A obviously decreased the phosphorylation of 4E-BP1 in matrine-treated cells. These findings suggested that matrine inhibits the activity of eIF4E by dephosphorylating 4E-BP1, which partly counts for the growth inhibition in gastric MKN45 cells.
苦参碱来源于苦参，在体外可显著抑制多种癌细胞的生长并诱导其凋亡。真核细胞起始因子4E（eIF4E）及其抑制剂4E结合蛋白1（4E-BP1）在调节mRNA翻译和细胞增殖中起关键作用。然而，苦参碱是否通过减弱4E-BP1的活性来抑制癌细胞生长仍不清楚。在本研究中，我们分析了苦参碱对胃癌MKN45细胞中4E-BP1和eIF4E的影响。免疫印迹显示，苦参碱以剂量和时间依赖性方式通过使4E-BP1去磷酸化来抑制eIF4E的活性。我们发现苦参碱使4E-BP1和eIF4E的上游调节因子细胞外信号调节激酶1/2（Erk1/2）失活，并显著降低4E-BP1和eIF4E的磷酸化水平，而4E-BP1受应激活化蛋白激酶（JNK）、p38或蛋白激酶B/哺乳动物雷帕霉素靶蛋白（Akt/mTOR）的影响较小。蛋白磷酸酶2A（PP2A）的失活明显降低了苦参碱处理细胞中4E-BP1的磷酸化水平。这些发现表明，苦参碱通过使4E-BP1去磷酸化来抑制eIF4E的活性，这在一定程度上解释了其对胃癌MKN45细胞生长的抑制作用。
