Department of Gastroenterology, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Biochem Pharmacol. 2011 Apr 1;81(7):910-6. doi: 10.1016/j.bcp.2011.01.005. Epub 2011 Jan 15.
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.
芬维 A 酯，一种合成维 A 酸，是一种有前途的抗癌药物，基于许多体外、动物和化学预防临床试验研究。然而，细胞如 HepG2 人肝癌细胞对芬维 A 酯的凋亡作用有抗性。以前，我们已经表明，芬维 A 酯诱导的凋亡依赖于 Nur77，并且癌细胞对芬维 A 酯诱导的凋亡的敏感性与 Nur77 的细胞质富集呈正相关。目前研究的目的是确定调节 Nur77 核输出的方法，以提高芬维 A 酯的疗效。芬维 A 酯处理使 Huh7 细胞中的 ERK1/2 失活，但激活 HepG2 细胞中的 ERK1/2，这与细胞对芬维 A 酯的凋亡作用的敏感性呈正相关。芬维 A 酯或 ERK1/2 抑制剂 PD98059 单独使用都不能影响 HepG2 细胞的存活，但两者的组合诱导细胞死亡并增加 caspase 3/7 活性。在芬维 A 酯敏感的 Huh7 细胞中，表皮生长因子 (EGF) 激活 ERK1/2 可防止芬维 A 酯诱导的细胞死亡和 caspase 3/7 诱导。此外，ERK1/2 的调节改变了 Nur77 的细胞内定位。芬维 A 酯/PD98059 诱导 HepG2 细胞死亡与 Nur77 的诱导和细胞质定位以及线粒体富集呈正相关。这种作用是特异性的 ERK1/2，因为其他丝裂原激活蛋白激酶如 P38、Akt 和 JNK 的磷酸化水平没有相关变化。总之，目前的研究表明，ERK1/2 调节的 Nur77 细胞内定位决定了芬维 A 酯诱导的凋亡的疗效。
