Translational Control Group, Division of Biomedical Sciences, St George's, University of London, London, SW17 0RE, UK.
Biol Cell. 2013 Sep;105(9):414-29. doi: 10.1111/boc.201300021. Epub 2013 Jul 16.
Tumour cells can be induced to undergo apoptosis after treatment with the tumour necrosis factor α-related death-inducing ligand (TRAIL). Although human pancreatic cancer cells show varying degrees of response they can be sensitised to the pro-apoptotic effects of TRAIL in the presence of celastrol, a natural compound extracted from the plant Tripterygium wilfordii Hook F. One important aspect of the cellular response to TRAIL is the control of protein synthesis, a key regulator of which is the eukaryotic initiation factor 4E-binding protein, 4E-BP1.
We examined the effects of celastrol and TRAIL in several pancreatic cancer cell lines. In cells that are normally resistant to TRAIL, synergistic effects of TRAIL plus celastrol on commitment to apoptosis and inhibition of protein synthesis were observed. These were associated with a strong up-regulation and dephosphorylation of 4E-BP1. The enhancement of 4E-BP1 expression, which correlated with a threefold increase in the level of the 4E-BP1 transcript, was blocked by inhibitors of reactive oxygen species and the JNK protein kinase. When the expression of 4E-BP1 was reduced by an inducible micro-RNA, TRAIL-mediated apoptosis was inhibited.
These results suggest that 4E-BP1 plays a critical role in the mechanism by which TRAIL and celastrol together cause apoptotic cell death in human pancreatic tumour cells.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）可诱导肿瘤细胞发生凋亡。尽管人胰腺癌细胞对 TRAIL 的反应程度不同，但在雷公藤红素（一种从植物雷公藤中提取的天然化合物）存在的情况下，它们可以对 TRAIL 的促凋亡作用产生敏感性。细胞对 TRAIL 反应的一个重要方面是控制蛋白质合成，其中一个关键调节因子是真核起始因子 4E 结合蛋白 1（4E-BP1）。
我们研究了雷公藤红素和 TRAIL 在几种胰腺癌细胞系中的作用。在通常对 TRAIL 有抗性的细胞中，TRAIL 加雷公藤红素对细胞凋亡的启动和蛋白质合成的抑制作用具有协同作用。这与 4E-BP1 的强烈上调和去磷酸化有关。4E-BP1 表达的增强与 4E-BP1 转录本水平增加三倍相关，这一增强被活性氧和 JNK 蛋白激酶抑制剂所阻断。当通过诱导型 micro-RNA 降低 4E-BP1 的表达时，TRAIL 介导的细胞凋亡受到抑制。
这些结果表明，4E-BP1 在 TRAIL 和雷公藤红素联合诱导人胰腺肿瘤细胞发生凋亡性细胞死亡的机制中起着关键作用。
