ERK1/2 deactivation enhances cytoplasmic Nur77 expression level and improves the apoptotic effect of fenretinide in human liver cancer cells.
ERK1/2 deactivation enhances cytoplasmic Nur77 expression level and improves the apoptotic effect of fenretinide in human liver cancer cells.
复制标题
ERK1/2失活增强细胞质Nur77表达水平并改善芬维A胺在人肝癌细胞中的凋亡作用。
DOI：
10.1016/j.bcp.2011.01.005
复制
发表时间：
2011-04-01
影响因子：
5.8
通讯作者：
Wan YJ
中科院分区：
文献类型：
--
作者：
Yang H;Nie Y;Li Y;Wan YJ
芬维A胺是一种合成类维生素A，是一种很有前途的抗癌药物，基于许多体外，动物和化学预防临床试验研究。然而，细胞如HepG 2人肝癌细胞对芬维A胺的凋亡作用具有抗性。以前，我们已经表明，芬维A胺诱导的细胞凋亡是Nur 77依赖性的，癌细胞对芬维A胺诱导的细胞凋亡的敏感性与Nur 77的细胞质富集呈正相关。本研究的目的是确定调节Nur 77核输出的方法，以提高芬维A胺的疗效。芬维A胺处理使Huh 7细胞中的ERK 1/2失活，但使HepG 2细胞中的ERK 1/2活化，这与细胞对芬维A胺的凋亡作用的敏感性正相关。单独使用芬维A胺或ERK 1/2抑制剂PD 98059均不能影响HepG 2细胞的存活，但两者联合使用可诱导细胞死亡并增加caspase 3/7活性。在芬维A胺敏感的Huh 7细胞中，表皮生长因子（EGF）激活ERK 1/2阻止了芬维A胺诱导的细胞死亡和caspase 3/7诱导。此外，ERK 1/2的调节改变了Nur 77的细胞内定位。芬维A胺/PD 98059诱导的HepG 2细胞死亡与Nur 77的诱导、胞浆定位以及线粒体富集呈正相关。这种效应对ERK 1/2是特异性的，因为其他促分裂原活化蛋白激酶如P38、Akt和JNK在其磷酸化水平上没有相关的变化。总之，目前的研究表明，ERK 1/2调节的Nur 77细胞内定位决定了芬维A胺诱导的细胞凋亡的功效。
Fenretinide, a synthetic retinoid, is a promising anticancer agent based on many in vitro, animal, and chemoprevention clinical trial studies. However, cells such as HepG2 human liver cancer cells are resistant to the apoptotic effect of fenretinide. Previously, we have shown that fenretinide-induced apoptosis is Nur77 dependent, and the sensitivity of the cancer cells to fenretinide-induced apoptosis is positively associated with cytoplasmic enrichment of Nur77. The goal of current study was to identify means to modulate nuclear export of Nur77 in order to improve the efficacy of fenretinide. Fenretinide treatment deactivated ERK1/2 in Huh7 cells, but activated ERK1/2 in HepG2 cells, which was positively associated with the sensitivity of cells to the apoptotic effect of fenretinide. Neither fenretinide nor ERK1/2 inhibitor PD98059 alone could affect the survival of HepG2 cells, but the combination of both induced cell death and increased caspase 3/7 activity. In fenretinide sensitive Huh7 cells, activation of ERK1/2 by epidermal growth factor (EGF) prevented fenretinide-induced cell death and caspase 3/7 induction. In addition, modulation of ERK1/2 changed the intracellular localization of Nur77. Fenretinide/PD98059-induced cell death of HepG2 cell was positively associated with induction and cytoplasmic location as well as mitochondria enrichment of Nur77. The effect was specific for ERK1/2 because other mitogen activated protein kinases such as P38, Akt, and JNK did not have correlated changes in their phosphorylation levels. Taken together, the current study demonstrates that ERK1/2-modulated Nur77 intracellular location dictates the efficacy of fenretinide-induced apoptosis.