The University of Arizona, Department of Pharmacology, 1501 N Campbell Ave., Tucson, AZ 85724, USA.
The University of Arizona, Department of Pharmacology, 1501 N Campbell Ave., Tucson, AZ 85724, USA.
Toxicol Appl Pharmacol. 2014 Apr 1;276(1):55-62. doi: 10.1016/j.taap.2014.01.013. Epub 2014 Jan 28.
Doxorubicin (Dox) is an indispensable chemotherapeutic agent for the treatment of various forms of neoplasia such as lung, breast, ovarian, and bladder cancers. Cardiotoxicity is a major concern for patients receiving Dox therapy. Previous work from our laboratory indicated that glucocorticoids (GCs) alleviate Dox-induced apoptosis in cardiomyocytes. Here we have found glucocorticoid-induced leucine zipper (GILZ) to be a mediator of GC-induced cytoprotection. GILZ was found to be induced in cardiomyocytes by GC treatment. Knocking down of GILZ using siRNA resulted in cancelation of GC-induced cytoprotection against apoptosis by Dox treatment. Overexpressing GILZ by transfection was able to protect cells from apoptosis induced by Dox as measured by caspase activation, Annexin V binding and morphologic changes. Western blot analyses indicate that GILZ overexpression prevented cytochrome c release from mitochondria and cleavage of caspase-3. When bcl-2 family proteins were examined, we found that GILZ overexpression causes induction of the pro-survival protein Bcl-xL. Since siRNA against Bcl-xL reverses GC induced cytoprotection, Bcl-xL induction represents an important event in GILZ-induced cytoprotection. Our data suggest that GILZ functions as a cytoprotective gene in cardiomyocytes.
阿霉素（Dox）是治疗肺癌、乳腺癌、卵巢癌和膀胱癌等多种形式肿瘤的不可或缺的化疗药物。心脏毒性是接受 Dox 治疗的患者的主要关注点。我们实验室的先前工作表明，糖皮质激素（GCs）可减轻 Dox 诱导的心肌细胞凋亡。在这里，我们发现糖皮质激素诱导亮氨酸拉链（GILZ）是 GC 诱导细胞保护的介质。GC 处理可诱导心肌细胞中 GILZ 的产生。使用 siRNA 敲低 GILZ 会导致 Dox 处理引起的细胞凋亡的 GC 诱导细胞保护作用丧失。通过转染过表达 GILZ 可保护细胞免受 Dox 诱导的细胞凋亡，如 caspase 激活、Annexin V 结合和形态变化所测量。Western blot 分析表明，GILZ 过表达可防止细胞色素 c 从线粒体释放和 caspase-3 的裂解。当检查 bcl-2 家族蛋白时，我们发现 GILZ 过表达可诱导存活蛋白 Bcl-xL 的产生。由于针对 Bcl-xL 的 siRNA 逆转了 GC 诱导的细胞保护作用，因此 Bcl-xL 的诱导代表了 GILZ 诱导的细胞保护中的重要事件。我们的数据表明，GILZ 在心肌细胞中作为一种细胞保护基因发挥作用。
