Myatt S S, Burchill S A
Candlelighter's Children's Cancer Research Laboratory, Cancer Research UK Clinical Centre, St James's University Hospital, Leeds, UK.
Oncogene. 2008 Feb 7;27(7):985-96. doi: 10.1038/sj.onc.1210705. Epub 2007 Aug 13.
The Ewing's sarcoma family of tumours (ESFT) are small round cell tumours characterized by the non-random EWS-ETS gene rearrangements. We have previously demonstrated that ESFT are highly sensitive to fenretinide-induced death, effected in part through a reactive oxygen species (ROS)-dependent pathway. Here, we demonstrate for the first time that the sensitivity of ESFT cells to fenretinide-induced cell death is decreased following downregulation of the oncogenic fusion protein EWS-Fli1; siRNA targeting EWS-Fli1 attenuated fenretinide-induced cell death in cell lines expressing EWS-Fli1, but not EWS-ERG. This decrease in cell death was independent of the level of ROS produced following exposure to fenretinide, but was effected through EWS-Fli1-dependent modulation of p38(MAPK) activity. Furthermore, inhibition of p38(MAPK) activity and knockdown of EWS-Fli1 reduced fenretinide-induced mitochondrial permeabilization, cytochrome c release, caspase and PARP cleavage, consistent with the hypothesis that p38(MAPK) is critical for activation of the death cascade by fenretinide in ESFT cells. These data demonstrate that expression of EWS-Fli1 enhances fenretinide-induced cell death in ESFT and that this is effected at least in part through modulation of p38(MAPK) activity.
尤因肉瘤家族性肿瘤（ESFT）是一类小细胞圆形肿瘤，其特征为非随机的EWS-ETS基因重排。我们之前已经证明，ESFT对芬维A胺诱导的死亡高度敏感，部分是通过活性氧（ROS）依赖的途径实现的。在此，我们首次证明，致癌融合蛋白EWS-Fli1下调后，ESFT细胞对芬维A胺诱导的细胞死亡的敏感性降低；靶向EWS-Fli1的小干扰RNA（siRNA）减弱了在表达EWS-Fli1而非EWS-ERG的细胞系中芬维A胺诱导的细胞死亡。这种细胞死亡的减少与暴露于芬维A胺后产生的ROS水平无关，而是通过EWS-Fli1依赖的p38（丝裂原活化蛋白激酶）活性调节实现的。此外，抑制p38（丝裂原活化蛋白激酶）活性和敲低EWS-Fli1可减少芬维A胺诱导的线粒体通透性转变、细胞色素c释放、半胱天冬酶和聚（ADP-核糖）聚合酶裂解，这与p38（丝裂原活化蛋白激酶）对ESFT细胞中芬维A胺激活死亡级联反应至关重要的假设一致。这些数据表明，EWS-Fli1的表达增强了ESFT中芬维A胺诱导的细胞死亡，并且这至少部分是通过调节p38（丝裂原活化蛋白激酶）活性实现的。
