Deubiquitylatinase inhibitor b-AP15 induces c-Myc-Noxa-mediated apoptosis in esophageal squamous cell carcinoma
Deubiquitylatinase inhibitor b-AP15 induces c-Myc-Noxa-mediated apoptosis in esophageal squamous cell carcinoma
复制标题
去泛素化酶抑制剂 b-AP15 诱导食管鳞状细胞癌中 c-Myc-Noxa 介导的细胞凋亡
DOI：
10.1007/s10495-019-01561-9
复制
发表时间：
2019-10-01
期刊：
影响因子：
7.2
通讯作者：
Li, Pei
中科院分区：
文献类型：
--
作者：
Sha, Beibei;Chen, Xiaoyu;Li, Pei
食道鳞状细胞癌(ESCC)是东亚地区最常见的恶性肿瘤之一。然而，其进展的分子机制仍不清楚。泛素-蛋白酶体系统(UPS)是蛋白质降解和周转的中心机制。越来越多的证据表明，越来越多的去泛素酶可以作为诱人的抗癌靶点。采用免疫组织化学和免疫印迹方法检测USP14和UCH37在食管鳞癌组织中的表达。采用细胞存活率实验检测USP14和UCH37抑制剂b-AP15对人食管癌细胞生长的影响。用b-AP15处理细胞后，进一步检测细胞周期、细胞凋亡及相关蛋白的表达，以探讨b-AP15抗ESCC的作用机制。结果表明，去泛素化酶(DUBS)USP14和UCH37在食管癌组织中的表达水平高于癌旁组织。B-AP15可抑制ESCC细胞增殖，诱导细胞周期停滞和凋亡。从机制上讲，b-AP15诱导的细胞凋亡依赖于Noxa，并受c-Myc的调控。沉默Noxa和c-Myc可减少b-AP15诱导的ESCC细胞凋亡。我们的结果揭示了b-AP15在食管癌中的抗肿瘤作用的新机制，b-AP15可以作为食管癌的潜在治疗药物。
Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors in east Asia. However, the molecular mechanism underlying its progression remains unclear. The ubiquitin-proteasome system (UPS) is a central mechanism for protein degradation and turnover. Accumulating evidence showed that more and more deubiquitinases could serve as attractive anti-cancer target. The expression of USP14 and UCH37 in esophagus squamous cell carcinoma tissues were examined by immunohistochemistry and western blot assays. Effect of b-AP15, a USP14 and UCH37 inhibitor, on ESCC cell growth was evaluated by cell viability assay. After cell lines being treated with b-AP15, cell cycle, apoptosis and the expression of related proteins were further explored to investigate the anti-ESCC mechanism of b-AP15. Results showed that deubiquitinating enzymes (DUBs) USP14 and UCH37 expressed at higher levels in ESCC tissues than in adjacent tissues. b-AP15 could inhibit cell proliferation and induce G2/M cell cycle arrest and apoptosis in ESCC cells. Mechanistically, b-AP15 treatment triggered Noxa-dependent apoptosis, which was regulated by c-Myc. Silencing Noxa and c-Myc could reduce b-AP15-induced apoptosis in ESCC cells. Our results revealed a novel mechanism of anti-tumor activity of b-AP15 in ESCC, and b-AP15 could be used as a potential therapeutic agent in ESCC.