Dual regulation of glucocorticoid-induced leucine zipper (GILZ) by the glucocorticoid receptor and the PI3-kinase/AKT pathways in multiple myeloma
Dual regulation of glucocorticoid-induced leucine zipper (GILZ) by the glucocorticoid receptor and the PI3-kinase/AKT pathways in multiple myeloma
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DOI：
10.1016/j.jsbmb.2007.11.003
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发表时间：
2008-06-01
影响因子：
4.1
通讯作者：
Rosen, Steven T.
中科院分区：
文献类型：
--
作者：
Grugan, Katharine D.;Ma, Chunguang;Rosen, Steven T.
糖皮质激素（GCs）是一种常用的治疗多发性骨髓瘤（MM）的有效药物。阐明气相色谱诱导细胞凋亡的途径对于理解耐药过程和开发新的MM治疗靶点至关重要。我们之前发表的微阵列研究结果表明，糖皮质激素诱导的亮氨酸拉链（GILZ）是MMAS细胞中gc调节的基因。与这些结果一致，GCs增加了MM细胞系和患者样品中的GILZ。用siRNA降低GILZ水平可减少gc诱导的细胞死亡，提示GILZ可能介导gc杀伤。我们进行了筛选，以确定影响GILZ调节的其他途径，并报告pi3 -激酶/AKT抑制剂增强了MM细胞系和临床样本中GILZ的表达。地塞米松（Dex）与LY294002、wortmannin、triciribine或AKT抑制剂VIII联合使用可显著上调GILZ水平，并促进细胞凋亡。白细胞介素-6 （IL-6）或胰岛素样生长因子（IGF1）的加入可激活pi3 -激酶/AKT通路并抑制GC杀伤，从而阻断GC和pi3 -激酶/AKT抑制剂对GILZ的调节。综上所述，这些结果确定了GILZ是GC杀伤的介质，表明pi3激酶/AKT在控制GILZ调节中的作用，并表明pi3激酶/AKT抑制剂和GCs的联合可能是一种有益的MM治疗方法。(C) 2008 Elsevier Ltd版权所有。
Glucocorticoids (GCs) are effective therapeutics commonly used in multiple myeloma (MM) treatment. Clarifying the pathway of GC-induced apoptosis is crucial to understanding the process of drug resistance and to the development of new targets for MM treatment. We have previously published results of a micro-array identifying glucocorticoid-induced leucine zipper (GILZ) as GC-regulated gene in MMAS cells. Consistent with those results, GCs increased GILZ in MM cell lines and patient samples. Reducing the levels of GILZ with siRNA decreased GC-induced cell death suggesting GILZ may mediate GC-killing. We conducted a screen to identify other pathways that affect GILZ regulation and report that inhibitors of PI3-kinase/AKT enhanced GILZ expression in MM cell lines and clinical samples. The combination of dexamethasone (Dex) and LY294002, wortmannin, triciribine, or AKT inhibitor VIII dramatically up regulated GILZ levels and enhanced apoptosis. Addition of interleukin-6 (IL-6) or insulin-like growth factor (IGF1), both which activate the PI3-kinase/AKT pathway and inhibit GC killing, blocked up regulation of GILZ by GC and PI3-kinase/AKT inhibitors. In summary, these results identify GILZ as a mediator of GC killing, indicate a role of PI3-kinase/AKT in controlling GILZ regulation and suggest that the combination of PI3-kinase/AKT inhibitors and GCs may be a beneficial MM treatment. (C) 2008 Elsevier Ltd. All rights reserved.