Celastrol (CSL) is a naturally occurring triterpenoid acid that exhibits anticancer activity, and in KU7 and 253JB-V bladder cells, CSL induced apoptosis, inhibited growth, colony formation and migration and CSL decreased bladder tumor growth in vivo. CSL also decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and several Sp-regulated genes/proteins including vascular endothelial growth factor, survivin and cyclin D1 and fibroblast growth factor receptor-3, a potential drug target for bladder cancer therapy, has now been characterized as an Sp-regulated gene downregulated by CSL. The mechanism of Sp downregulation by CSL was cell context-dependent due to activation of proteosome-dependent (KU7) and -independent (253JB-V) pathways. In 253JB-V cells, CSL induced reactive oxygen species (ROS) and inhibitors of ROS blocked CSL-induced growth inhibition and repression of Sp1, Sp3 and Sp4. This response was due to induction of the Sp repressors ZBTB10 and ZBTB4 and downregulation of miR-27a and miR-20a/17-5p, respectively, which regulate expression of these transcriptional repressors. Thus, the anticancer activity of CSL in 253JB-V cells is due to induction of ROS and ROS-mediated induction of Sp repressors (ZBTB4/ZBTB10) through downregulation of miR-27a and miR-20a/17-5p.

译文

:Celastrol(CSL)是天然存在的三萜酸,具有抗癌活性,在KU7和253JB-V膀胱细胞中,CSL诱导凋亡,抑制生长,集落形成和迁移,并降低体内膀胱肿瘤的生长。 CSL还降低了特异性蛋白(Sp)转录因子Sp1,Sp3和Sp4以及一些Sp调控的基因/蛋白的表达,包括血管内皮生长因子,survivin和cyclin D1和成纤维细胞生长因子受体3,这是膀胱癌的潜在药物靶标现在,这种疗法的特征是被CSL下调了Sp调控的基因。 CSL对Sp的下调机制是由于蛋白体依赖性(KU7)和非依赖性(253JB-V)途径的激活而与细胞环境有关。在253JB-V细胞中,CSL诱导了活性氧(ROS),ROS抑制剂阻止了CSL诱导的Sp1,Sp3和Sp4的生长抑制和抑制。该应答是由于分别诱导Sp阻遏物ZBTB10和ZBTB4的诱导以及miR-27a和miR-20a / 17-5p的下调,它们分别调节这些转录阻遏物的表达。因此,CSL在253JB-V细胞中的抗癌活性是由于通过下调miR-27a和miR-20a / 17-5p诱导了ROS和ROS介导的Sp阻遏物(ZBTB4 / ZBTB10)的诱导。

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