College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, 450001, China.
Apoptosis. 2019 Oct;24(9-10):826-836. doi: 10.1007/s10495-019-01561-9.
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.
食管鳞状细胞癌（ESCC）是东亚地区最恶性的肿瘤之一。然而，其进展的分子机制尚不清楚。泛素-蛋白酶体系统（UPS）是蛋白质降解和周转的核心机制。越来越多的证据表明，越来越多的去泛素化酶可以作为有吸引力的抗癌靶点。通过免疫组织化学和 Western blot 检测 USP14 和 UCH37 在食管鳞状细胞癌组织中的表达。通过细胞活力测定评估 USP14 和 UCH37 抑制剂 b-AP15 对 ESCC 细胞生长的影响。在用 b-AP15 处理细胞系后，进一步探讨细胞周期、细胞凋亡和相关蛋白的表达，以研究 b-AP15 的抗 ESCC 机制。结果表明，去泛素化酶（DUBs）USP14 和 UCH37 在 ESCC 组织中的表达水平高于相邻组织。b-AP15 可抑制 ESCC 细胞的增殖，并诱导 G2/M 细胞周期阻滞和凋亡。机制上，b-AP15 处理触发了依赖 Noxa 的凋亡，这受 c-Myc 调节。沉默 Noxa 和 c-Myc 可减少 b-AP15 诱导的 ESCC 细胞凋亡。我们的研究结果揭示了 b-AP15 在 ESCC 中的抗肿瘤活性的新机制，b-AP15 可作为 ESCC 的潜在治疗剂。
