Rapamycin sensitizes T-ALL cells to dexamethasone-induced apoptosis.
Rapamycin sensitizes T-ALL cells to dexamethasone-induced apoptosis.
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雷帕霉素使 T-ALL 细胞对地塞米松诱导的细胞凋亡敏感
DOI：
10.1186/1756-9966-29-150
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发表时间：
2010-11-18
期刊：
影响因子：
--
通讯作者：
Ma Z
中科院分区：
文献类型：
--
作者：
Gu L;Zhou C;Liu H;Gao J;Li Q;Mu D;Ma Z
研究背景糖皮质激素（GC）抵抗常见于T细胞系急性淋巴细胞白血病（T-ALL）。在这项研究中，我们探讨的潜力和机制，雷帕霉素，以恢复敏感的GC-耐药的T-ALL细胞地塞米松（Dex）treatment.MethodsCell增殖3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四氮唑溴化物（MTT）法检测。流式细胞仪（FACS）分析细胞凋亡和细胞周期。结果10 nM雷帕霉素可显著增加耐药T-ALL细胞对GC的敏感性，其作用可能与抑制mTOR信号通路有关。细胞周期阻滞与G1-S期调节因子的调节有关。雷帕霉素和Dex都能诱导p21和p27的细胞周期蛋白依赖性激酶（CDK）抑制剂的上调，雷帕霉素与Dex的共同处理导致其表达的协同诱导。雷帕霉素对细胞周期蛋白A的表达无明显影响，而地塞米松诱导细胞周期蛋白A的表达。雷帕霉素阻止Dex诱导的细胞周期蛋白A的表达。雷帕霉素对cyclin D1表达的抑制作用强于地塞米松。雷帕霉素增强GC诱导的细胞凋亡，这不是通过调节糖皮质激素受体（GR）表达实现的，而是通过协同上调促凋亡蛋白如caspase-3、Bax和Bim来实现的，结论雷帕霉素能有效逆转T-ALL的GC耐药，其作用机制可能是通过诱导T-ALL细胞周期阻滞于G 0/G2期而实现的。G1期，激活内在的凋亡程序。因此，mTOR抑制剂雷帕霉素联合GC方案可能是GC耐药T-ALL患者的一种新的治疗方法。
BackgroundGlucocorticoid (GC) resistance is frequently seen in acute lymphoblastic leukemia of T-cell lineage (T-ALL). In this study we investigate the potential and mechanism of using rapamycin to restore the sensitivity of GC-resistant T-ALL cells to dexamethasone (Dex) treatment.MethodsCell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay. Fluorescence-activated cell sorting (FACS) analysis was used to analyze apoptosis and cell cycles. Western blot analysis was performed to test the expression of the downstream effector proteins of mammalian target of rapamycin (mTOR), the cell cycle regulatory proteins, and apoptosis associated proteins.Results10 nM rapamycin markedly increased GC sensitivity in GC-resistant T-ALL cells and this effect was mediated, at least in part, by inhibition of mTOR signaling pathway. Cell cycle arrest was associated with modulation of G1-S phase regulators. Both rapamycin and Dex can induce up-regulation of cyclin-dependent kinase (CDK) inhibitors of p21 and p27 and co-treatment of rapamycin with Dex resulted in a synergistic induction of their expressions. Rapamycin did not obviously affect the expression of cyclin A, whereas Dex induced cyclin A expression. Rapamycin prevented Dex-induced expression of cyclin A. Rapamycin had a stronger inhibition of cyclin D1 expression than Dex. Rapamycin enhanced GC-induced apoptosis and this was not achieved by modulation of glucocorticoid receptor (GR) expression, but synergistically up-regulation of pro-apoptotic proteins like caspase-3, Bax, and Bim, and down-regulation of anti-apoptotic protein of Mcl-1.ConclusionOur data suggests that rapamycin can effectively reverse GC resistance in T-ALL and this effect is achieved by inducing cell cycles arrested at G0/G1phase and activating the intrinsic apoptotic program. Therefore, combination of mTOR inhibitor rapamycin with GC containing protocol might be an attracting new therapeutic approach for GC resistant T-ALL patients.
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