Dexamethasone inhibits camptothecin-induced apoptosis in C6-glioma via activation of Stat5/Bcl-xL pathway.
Dexamethasone inhibits camptothecin-induced apoptosis in C6-glioma via activation of Stat5/Bcl-xL pathway.
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DOI：
10.1016/j.bbamcr.2009.01.017
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发表时间：
2009-05
期刊：
影响因子：
--
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Qian YH;Xiao Q;Chen H;Xu J
地塞米松（DX）在与化疗药物（如喜树碱（CAM））联合治疗期间诱导大多数实体恶性肿瘤的凋亡抵抗。在这项研究中，我们研究了DX降低C6胶质瘤化疗效率的机制。DX减少CAM增加的DNA片段化和caspase-3激活。糖皮质激素受体（GR）拮抗剂RU 486可阻断DX的保护作用。DX本身增加了抗凋亡基因Bcl-xL的表达及其转录因子、信号转导和转录激活因子5（Stat 5）、DNA结合活性和磷酸化Stat 5的表达。DX阻断CAM降低的Bcl-xL和磷酸化Stat 5表达以及Stat 5结合活性。RU 486否定了DX的行动。为了确定Stat 5是否调节CAM诱导的细胞死亡中的Bcl-xL表达，用含有组成型激活的Stat 5-GFP（Ad-Stat 5ca）的腺病毒感染C6神经胶质瘤。与对照腺病毒感染的细胞相比，Stat 5ca的过表达增加Bcl-xL并降低CAM诱导的细胞死亡;而Stat 5 siRNA降低DX诱导的Bcl-xL并增加细胞死亡。通过与抗GR抗体的免疫共沉淀，在核提取物中观察到磷酸化Stat 5表达，表明Stat 5和GR相互作用并在核中形成复合物。以上结果提示，DX对CAM诱导的细胞凋亡的保护作用及RU 486对DX保护作用的拮抗作用可能是通过GR调控的Stat 5/Bcl-xL信号通路实现的。
Dexamethasone (DX) induces apoptosis resistance in most solid malignant tumors during co-treatment with chemotherapy agents, such as camptothecin (CAM). In this study, we investigated the mechanism by which DX reduces chemotherapy efficiency in C6-glioma. DX reduced CAM-increased DNA fragmentation and caspase-3 activation. The DX’s protection was negated by RU486, an antagonist of glucocorticoid receptor (GR). DX itself increased anti-apoptotic gene, Bcl-xL expression, and its transcription factor, signaling transducer and activator of transcription 5 (Stat5), DNA binding activity and phospho-Stat5 expression. DX blocked the CAM-decreased Bcl-xL and phospho-Stat5 expression, and Stat5 binding activity. RU486 negated DX’s actions. To determine whether Stat5 regulates Bcl-xL expression in CAM -induced cell death, C6-glioma was infected with an adenovirus containing a constitutively activated Stat5-GFP (Ad-Stat5ca). Overexpression of Stat5ca increased Bcl-xL and decreased CAM-induced cell death compared to control adenovirus infected cells; whereas Stat5 siRNA decreased DX-induced Bcl-xL and increased cell death. Phospho-Stat5 expression was observed in the nuclear extract by co-immunoprecipitation with an anti-GR antibody, indicating that Stat5 and GR were interactive and formed a complex in the nuclei. These results suggest that DX’s prevention from CAM -induced apoptosis and RU486’s antagonism of DX’s protection may be through Stat5/Bcl-xL signal pathway regulated by a GR.
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