Nitric oxide sensitizes tumor cells to TRAIL-induced apoptosis via inhibition of the DR5 transcription repressor Yin Yang 1
Nitric oxide sensitizes tumor cells to TRAIL-induced apoptosis via inhibition of the DR5 transcription repressor Yin Yang 1
复制标题
DOI：
10.1016/j.niox.2008.08.001
复制
发表时间：
2009-02-01
影响因子：
3.9
通讯作者：
Bonavida, Benjamin
中科院分区：
文献类型：
--
作者：
Huerta-Yepez, Sara;Vega, Mario;Bonavida, Benjamin
用一氧化氮供体DETANONOate处理TRAIL抗性肿瘤细胞使肿瘤细胞对TRAIL诱导的凋亡敏感，同时伴有DR 5上调。基于DETANONOate抑制负调节DR 5转录的转录阻遏物Yin Yang 1（YY 1）的假设，检查了致敏机制。用DETANONOate处理前列腺癌细胞系抑制NF-κ B和YY 1 DNA结合活性，同时上调DR 5表达。YY 1在调节TRAIL抗性中的直接作用在用YY 1 siRNA处理的细胞中得到证实，导致TRAIL诱导的凋亡。在用DR 5荧光素酶报告系统（pDR 5）和两种构建体处理的细胞中检测YY 1在DR 5转录调节中的作用，所述两种构建体即缺失推定的YY 1 DNA结合区（-1224至-605）的pDR 5/-605构建体和具有YY 1 DNA结合位点突变的构建体pDR 5-YY 1。在用修饰的构建体转染的细胞中观察到荧光素酶活性相对于用pDR 5的基线转染的显著（3倍）增强。ChIP分析证实YY 1与DRS启动子结合。在体内，来自携带PC-3异种移植物并用DETANONOate处理的裸鼠的组织显示YY 1的抑制和DRS的上调。本研究结果表明YY 1负调节DR 5的转录和表达，这些与对TRAIL诱导的细胞凋亡的抗性相关。DETANONOate抑制NF-κ B和YY 1，并与TRAIL联合逆转肿瘤细胞对TRAIL凋亡的抗性。(c)2008年爱思唯尔公司All rights reserved.
Treatment of TRAIL-resistant tumor cells with the nitric oxide donor DETANONOate sensitizes the tumor cells to TRAIL-induced apoptosis concomitantly with DR5 upregulation. The mechanism of sensitization was examined based on the hypothesis that DETANONOate inhibits a transcription repressor Yin Yang 1 (YY1) that negatively regulates DR5 transcription. Treatment of the prostate carcinoma cell lines with DETANONOate inhibited both NF-kappa B and YY1 DNA-binding activities concomitantly with upregulation of DR5 expression. The direct role of YY1 in the regulation of TRAIL resistance was demonstrated in cells treated with YY1 siRNA resulting in TRAIL-induced apoptosis. The role of YY1 in the transcriptional regulation of DR5 was examined in cells treated with a DR5 luciferase reporter system (pDR5) and two constructs, namely, the pDR5/-605 construct with a deletion of the putative YY1 DNA-binding region (-1224 to -605) and a construct pDR5-YY1 with a mutation of the YY1 DNA-binding site. A significant (3-fold) augmentation of luciferase activity over baseline transfection with pDR5 was observed in cells transfected with the modified constructs. ChIP analysis corroborated the YY1 binding to the DRS promoter. In vivo, tissues from nude mice bearing the PC-3 xenograft and treated with DETANONOate showed inhibition of YY1 and upregulation of DRS. The present findings demonstrate that YY1 negatively regulates DR5 transcription and expression and these correlated with resistance to TRAIL-induced apoptosis. DETANONOate inhibits both NF-kappa B and YY1 and in combination with TRAIL reverses tumor cell resistance to TRAIL apoptosis. (c) 2008 Elsevier Inc. All rights reserved.