A novel Hsp90 inhibitor AT13387 induces senescence in EBV-positive nasopharyngeal carcinoma cells and suppresses tumor formation.
A novel Hsp90 inhibitor AT13387 induces senescence in EBV-positive nasopharyngeal carcinoma cells and suppresses tumor formation.
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DOI：
10.1186/1476-4598-12-128
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发表时间：
2013-10-24
期刊：
影响因子：
37.3
通讯作者：
Mak NK
中科院分区：
文献类型：
--
作者：
Chan KC;Ting CM;Chan PS;Lo MC;Lo KW;Curry JE;Smyth T;Lee AW;Ng WT;Tsao GS;Wong RN;Lung ML;Mak NK
鼻咽癌（Nasopharyngeal carcinoma，NPC）是一种与EB病毒（Epstein-Barr virus，EBV）密切相关的上皮性恶性肿瘤。AT 13387是一种新型的热休克蛋白90（Hsp 90）抑制剂，可抑制Hsp 90的分子伴侣功能，并减少Hsp 90依赖的客户癌蛋白的表达。本研究旨在评价AT 13387在EBV阳性NPC细胞系C666-1中的体外和体内抗肿瘤作用。我们的研究结果表明，AT 13387抑制C666-1细胞生长，诱导细胞衰老，下调多种Hsp 90客户癌蛋白EGFR，AKT，CDK 4，并恢复细胞周期负调控因子p27的蛋白表达。我们还研究了AT 13387通过使用AKT抑制剂和Skp 2 siRNA下调AKT和p27泛素介导剂Skp 2来恢复p27表达的能力。在功能研究中，AT 13387通过下调细胞迁移调节剂HDAC 6抑制细胞迁移，并增加α-微管蛋白的乙酰化和稳定化。我们还通过3-D肿瘤球形成试验检查了AT 13387对推定的癌症干细胞（CSC）的影响。AT 13387有效减少了C666-1肿瘤球的数量和大小，降低了NPC CSC样标志物CD 44和SOX 2的表达。在体内研究中，AT 13387显著抑制了C666-1 NPC异种移植物中的肿瘤形成。AT 13387抑制EB病毒阳性NPC细胞系C666-1的细胞生长、细胞迁移、肿瘤球形成并诱导细胞衰老。此外，在体内模型中证明了AT 13387的抗肿瘤作用。本研究为AT 13387作为一种有效的抗肿瘤药物治疗鼻咽癌的临床前价值提供了实验依据。
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy strongly associated with Epstein-Barr virus (EBV). AT13387 is a novel heat shock protein 90 (Hsp90) inhibitor, which inhibits the chaperone function of Hsp90 and reduces expression of Hsp90-dependent client oncoproteins. This study aimed to evaluate both the in vitro and in vivo antitumor effects of AT13387 in the EBV-positive NPC cell line C666-1. Our results showed that AT13387 inhibited C666-1 cell growth and induced cellular senescence with the downregulation of multiple Hsp90 client oncoproteins EGFR, AKT, CDK4, and restored the protein expression of negative cell cycle regulator p27. We also studied the ability of AT13387 to restore p27 expression by downregulation of AKT and the p27 ubiquitin mediator, Skp2, using AKT inhibitor and Skp2 siRNA. In the functional study, AT13387 inhibited cell migration with downregulation of a cell migration regulator, HDAC6, and increased the acetylation and stabilization of α-tubulin. We also examined the effect of AT13387 on putative cancer stem cells (CSC) by 3-D tumor sphere formation assay. AT13387 effectively reduced both the number and size of C666-1 tumor spheres with decreased expression of NPC CSC-like markers CD44 and SOX2. In the in vivo study, AT13387 significantly suppressed tumor formation in C666-1 NPC xenografts. AT13387 suppressed cell growth, cell migration, tumor sphere formation and induced cellular senescence on EBV-positive NPC cell line C666-1. Also, the antitumor effect of AT13387 was demonstrated in an in vivo model. This study provided experimental evidence for the preclinical value of using AT13387 as an effective antitumor agent in treatment of NPC.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
--
作者：
Aldana-Masangkay GI;Sakamoto KM
通讯作者：
Sakamoto KM
影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
DOI：
10.1002/hed.20833
发表时间：
2008-07
影响因子：
2.9
作者：
Chou, Josephine;Lin, Yu-Ching;Kim, Jae;You, Liang;Xu, Zhidong;He, Biao;Jablons, David M.
通讯作者：
Jablons, David M.
CD44+与EBV相关的鼻咽癌中的癌症干细胞。
影响因子：
3.7
作者：
Lun SW;Cheung ST;Cheung PF;To KF;Woo JK;Choy KW;Chow C;Cheung CC;Chung GT;Cheng AS;Ko CW;Tsao SW;Busson P;Ng MH;Lo KW
通讯作者：
Lo KW