Smac Mimetics in Combination with TRAIL Selectively Target Cancer Stem Cells in Nasopharyngeal Carcinoma
Smac Mimetics in Combination with TRAIL Selectively Target Cancer Stem Cells in Nasopharyngeal Carcinoma
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Smac 模拟物与 TRAIL 组合选择性靶向鼻咽癌中的癌症干细胞
DOI：
10.1158/1535-7163.mct-13-0017
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发表时间：
2013-09-01
影响因子：
5.7
通讯作者：
Yang, Dajun
中科院分区：
文献类型：
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作者：
Wu, Man-si;Wang, Guang-feng;Yang, Dajun
鼻咽癌是中国南方常见的恶性肿瘤。放疗和化疗后，相当比例的鼻咽癌患者出现肿瘤复发和转移。肿瘤干细胞（Cancer stem cells， CSC）已显示出对治疗的耐药性，因此被认为是肿瘤复发和转移的发起者，其中CSC的抗凋亡特性起着重要作用。Smac/DIABLO是凋亡蛋白家族抑制剂（IAP）的逆调控因子，参与细胞凋亡。本研究以两个克隆的鼻咽癌细胞系CNE2为模型，在体外和体内研究了Smac模拟物对鼻咽癌CSCs的影响。我们发现其中一个克隆S18具有类似csc的特性，并且iap过表达。Smac模拟物与tnf相关凋亡诱导配体（TRAIL）联合使用可降低SP细胞的百分比，抑制S18细胞的集落和成球能力，表明其具有减弱CSCs的能力。此外，在鼻咽癌异种移植模型中，Smac模拟物联合TRAIL也导致鼻咽癌干细胞的消除。此外，Smac模拟物与TRAIL联合可诱导cIAP1和XIAP降解，从而诱导体外和体内细胞凋亡。综上所述，我们的数据表明，Smac模拟物对鼻咽癌干细胞具有抗肿瘤作用，这种联合治疗应该被认为是治疗鼻咽癌的一种有前景的策略。巨蟹座；12 (9);1728 - 37。AACR©2013。
Nasopharyngeal carcinoma is a common malignancy in Southern China. After radiotherapy and chemotherapy, a considerable proportion of patients with nasopharyngeal carcinoma suffered tumor relapse and metastasis. Cancer stem cells (CSC) have been shown with resistance against therapies and thus considered as the initiator of recurrence and metastasis in tumors, where the antiapoptotic property of CSCs play an important role. Smac/DIABLO is an inverse regulator for the inhibitors of apoptosis protein family (IAP), which have been involved in apoptosis. Here, the effects of Smac mimetics on the CSCs of nasopharyngeal carcinoma were studied both in vitro and in vivo, using two clones of nasopharyngeal carcinoma cell line CNE2 as models. We found that one of the clones, S18, had CSC-like properties and IAPs were overexpressed. The combination of Smac mimetics and TNF-related apoptosis-inducing ligand (TRAIL) can reduce the percentage of SP cells and inhibit the colony- and sphere-forming abilities of S18 cells, indicating their ability to attenuate the CSCs. Moreover, in a nasopharyngeal carcinoma xenograft model, the administration of Smac mimetics in combination with TRAIL also led to the elimination of nasopharyngeal carcinoma stem cells. Furthermore, the Smac mimetics in combination with TRAIL induced the degradation of cIAP1 and XIAP and thus induced apoptosis in vitro and in vivo. Taken together, our data show that Smac mimetics exerted an antitumor effect on nasopharyngeal carcinoma cancer stem cells, and this combination treatment should be considered as a promising strategy for the treatment of nasopharyngeal carcinoma. Mol Cancer Ther; 12(9); 1728–37. ©2013 AACR.