Role of Smac in Determining the Chemotherapeutic Response of Esophageal Squamous Cell Carcinoma
Role of Smac in Determining the Chemotherapeutic Response of Esophageal Squamous Cell Carcinoma
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Smac 在确定食管鳞状细胞癌化疗反应中的作用
DOI：
10.1158/1078-0432.ccr-11-0426
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发表时间：
2011-08-15
影响因子：
11.5
通讯作者：
Zhao, Xiaohang
中科院分区：
文献类型：
--
作者：
Xu, Yang;Zhou, Lanping;Zhao, Xiaohang
目的：第二类caspase激活因子（Smac）调节化疗诱导的细胞凋亡。Smac模拟物已在临床试验中作为化疗增敏剂进行了测试。我们确定了Smac在调节食管鳞状细胞癌（ESCC）化疗敏感性中的作用。实验设计：Smac的表达进行了评估，在组织中的ESCC患者与差异化疗反应。Smac敲除和Smac模拟物对ESCC细胞的化学敏感性的影响以及Smac和Smac模拟物调节化学敏感性的分子机制被确定。使用异种移植模型比较具有不同Smac状态的ESCC细胞的治疗反应。结果如下：Smac在食管鳞癌中的表达显著下调（36.8%，25/68，P = 0.001），且在化疗敏感性和耐药性食管鳞癌中的表达差异有统计学意义（P < 0.05）。使用逻辑回归分析测试的因素和他们的反应的协会进行了检查。在ESCC细胞用顺铂，一种常见的化疗药物，Smac和细胞色素c从线粒体释放，caspase-3和caspase-9被激活。敲除Smac可消除顺铂诱导的细胞凋亡、线粒体功能障碍、细胞色素c释放和半胱天冬酶激活。Smac缺陷也降低了顺铂对长期细胞活力的影响，并导致体内异种移植肿瘤中的顺铂耐药性。小分子Smac模拟物LBW 242可增强顺铂诱导的细胞凋亡和caspase激活，并恢复Smac缺陷细胞对顺铂的敏感性。结论：Smac表达下调可能是食管鳞癌化疗耐药的机制之一。Smac模拟物与化疗剂的组合可具有用于治疗食管癌的治疗益处。Clin Cancer Res; 17（16）; 5412-22.©2011 AACR。
Purpose: Second mitochondria-derived activator of caspase (Smac) regulates chemotherapy-induced apoptosis. Smac mimetics have been tested in clinical trials as chemosensitizers. We determined the role of Smac in modulating the chemosensitivity of esophageal squamous cell carcinoma (ESCC). Experimental Design: Smac expression was evaluated in tissues from ESCC patients with differential chemotherapeutic responses. The effects of Smac knockdown and Smac mimetics on the chemosensitivity of ESCC cells and the molecular mechanisms by which Smac and Smac mimetics modulate chemosensitivity were determined. The therapeutic responses of ESCC cells with different Smac statuses were compared using xenograft models. Results: We found that Smac was significantly downregulated in most ESCC samples (36.8%, 25/68, P = 0.001), and Smac expression differed significantly (P < 0.05) between chemosensitive and chemoresistant tumors. The associations of tested factors and their responses were examined using logistic regression analysis. In ESCC cells treated with cisplatin, a common chemotherapeutic drug, Smac and cytochrome c were released from mitochondria, and caspase-3 and caspase-9 were activated. Knockdown of Smac abrogated cisplatin-induced apoptosis, mitochondrial dysfunction, cytochrome c release, and caspase activation. Smac deficiency also reduced the effect of cisplatin on long-term cell viability, and led to cisplatin resistance in xenograft tumors in vivo. LBW242, a small molecule Smac mimetic, enhanced cisplatin-induced apoptosis and caspase activation and restored cisplatin sensitivity in Smac-deficient cells. Conclusion: Our data suggested that downregulation of Smac may be a chemoresistance mechanism in ESCC. Combinations of Smac mimetics with chemotherapeutic agents may have therapeutic benefits for the treatment of esophageal cancer. Clin Cancer Res; 17(16); 5412–22. ©2011 AACR.