IKK inhibition by BMS-345541 suppresses breast tumorigenesis and metastases by targeting GD2+ cancer stem cells.
IKK inhibition by BMS-345541 suppresses breast tumorigenesis and metastases by targeting GD2+ cancer stem cells.
复制标题
DOI：
10.18632/oncotarget.16294
复制
发表时间：
2017-06-06
期刊：
影响因子：
--
通讯作者：
Andreeff M
中科院分区：
文献类型：
--
作者：
Battula VL;Nguyen K;Sun J;Pitner MK;Yuan B;Bartholomeusz C;Hail N;Andreeff M
我们已经确定神经节苷脂GD 2是乳腺癌干细胞（BCSC）的标志物，靶向GD 3合酶（GD 3S，调节GD 2生物合成）可减少乳腺肿瘤的发生。调节GD 2表达的途径及其在BCSC中的异常功能尚不清楚。对来自乳腺癌细胞系的GD 2+和GD 2-细胞的蛋白质组学分析揭示了NFκB信号在GD 2+细胞中的活化。小分子抑制剂BMS-345541对NFκB信号传导的剂量和时间依赖性抑制使GD 2+细胞减少> 90%。同样，BMS-345541在体外抑制BCSC GD 3S表达、乳腺球形成和细胞迁移/侵袭。与对照小鼠相比，BMS-345541给药的乳腺肿瘤荷瘤小鼠显示肿瘤体积统计学显著性降低，并显示生存期延长，BMS-345541给药组的中位生存期为78天，对照组为58天。此外，在实验转移模型中，用BMS-345541治疗使肺转移减少> 5倍。这些数据表明GD 2的表达和功能以及NFκB信号传导是相关的，并且它们控制BCSC的致瘤特性。因此，BMS-345541对NFκB信号传导的抑制是控制乳腺癌生长和转移的潜在重要进展。
We have identified that the ganglioside GD2 is a marker for breast cancer stem cells (BCSCs), and that targeting the enzyme GD3 synthase (GD3S, which regulates GD2 biosynthesis) reduces breast tumorigenesis. The pathways regulating GD2 expression, and their anomalous functions in BCSC, are unclear. Proteomic analysis of GD2+ and GD2- cells from breast cancer cell lines revealed the activation of NFκB signaling in GD2+ cells. Dose- and time-dependent suppression of NFκB signaling by the small molecule inhibitor BMS-345541 reduced GD2+ cells by > 90%. Likewise, BMS-345541 inhibited BCSC GD3S expression, mammosphere formation, and cell migration/invasion in vitro. Breast tumor-bearing mice treated with BMS-345541 showed a statistically significant decrease in tumor volume and exhibited prolonged survival compared to control mice, with a median survival of 78 d for the BMS-345541-treated group vs. 58 d for the controls. Moreover, in an experimental metastases model, treatment with BMS-345541 reduced the lung metastases by > 5-fold. These data suggest that GD2 expression and function, and NFκB signaling, are related, and they control BCSCs tumorigenic characteristics. Thus, the suppression of NFκB signaling by BMS-345541 is a potentially important advance in controlling breast cancer growth and metastases.