Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Biochem Pharmacol. 2010 Apr 1;79(7):948-54. doi: 10.1016/j.bcp.2009.11.004. Epub 2009 Nov 11.
Fenretinide, a synthetic retinoid, is known to induce apoptosis in various cancer cells. However, the mechanism by which fenretinide induces apoptosis remains unclear. The current study examines the mechanisms of fenretinide-induced apoptosis in human hepatoma cells. The induction of Nur77 and the cytoplasmic distribution of Nur77 induced by fenretinide were positively correlated with the apoptotic effect of fenretinide in HCC cells. The sensitivity of Huh-7 cells was related to Nur77 translocation and targeting mitochondria, whereas the mechanism of resistance for HepG2 cells seemed due to Nur77 accumulating in the nucleus. The intracellular location of Nur77 was also associated with the differential capability of fenretinide-induced ROS generation in these two cell lines. In addition, the knockdown of Nur77 expression by siRNA greatly reduced fenretinide-induced apoptosis and cleaved caspase 3 in Huh-7 cells. Therefore, our findings demonstrate that fenretinide-induced apoptosis of HCC cells is Nur77 dependent and that the intracellular localization of Nur77 dictates the sensitivity of the HCC cells to fenretinide-induced apoptosis.
芬维 A 酯，一种合成维 A 酸，已知可诱导各种癌细胞凋亡。然而，芬维 A 酯诱导凋亡的机制尚不清楚。本研究探讨了芬维 A 酯诱导人肝癌细胞凋亡的机制。芬维 A 酯诱导的 Nur77 诱导和 Nur77 的细胞质分布与芬维 A 酯在 HCC 细胞中的凋亡作用呈正相关。Huh-7 细胞的敏感性与 Nur77 易位和靶向线粒体有关，而 HepG2 细胞的耐药机制似乎是由于 Nur77 积累在核内。Nur77 的细胞内位置也与这两种细胞系中芬维 A 酯诱导 ROS 生成的不同能力有关。此外，siRNA 下调 Nur77 表达可显著减少 Huh-7 细胞中芬维 A 酯诱导的凋亡和裂解的 caspase 3。因此，我们的研究结果表明，芬维 A 酯诱导 HCC 细胞凋亡依赖于 Nur77，并且 Nur77 的细胞内定位决定了 HCC 细胞对芬维 A 酯诱导凋亡的敏感性。
