Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing 100142, China.
Department of Oncology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, Guangdong, 518036, China.
Cancer Lett. 2018 Apr 10;419:64-74. doi: 10.1016/j.canlet.2018.01.051.
c-Myc amplification-induced cell cycle dysregulation is a common cause for esophageal squamous cell carcinoma (ESCC), but no approved targeted drug is available so far. The bromodomain inhibitor JQ1, which targets c-Myc, exerts anti-tumor activity in multiple cancers. However, the role of JQ1 in ESCC remains unknown. In this study, we reported that JQ1 had potent anti-proliferative effects on ESCC cells in both time- and dose-dependent manners by inducing cell cycle arrest at G1 phase, cell apoptosis, and the mesenchymal-epithelial transition. Follow-up studies revealed that both c-Myc/cyclin/Rb and PI3K/AKT signaling pathways were inactivated by JQ1, as indicated by the downregulation of c-Myc, cyclin A/E, and phosphorylated Rb, AKT and S6. Tumor suppression induced by JQ1 in c-Myc amplified or highly expressed xenografts was higher than that in xenografts with low expression, suggesting its potential role in prediction. In conclusion, targeting c-Myc by JQ1 could cause significant tumor suppression in ESCC both in vitro and in vivo. Also, c-Myc amplification or high expression might serve as a potential biomarker and provide a promising therapeutic option for ESCC.
c-Myc 扩增诱导的细胞周期失调是食管鳞状细胞癌（ESCC）的常见原因，但迄今为止尚无批准的靶向药物。靶向 c-Myc 的溴结构域抑制剂 JQ1 在多种癌症中具有抗肿瘤活性。然而，JQ1 在 ESCC 中的作用尚不清楚。在这项研究中，我们报道 JQ1 通过诱导 G1 期细胞周期阻滞、细胞凋亡和间质-上皮转化，以时间和剂量依赖的方式对 ESCC 细胞具有很强的抗增殖作用。后续研究表明，JQ1 通过下调 c-Myc、细胞周期蛋白 A/E 和磷酸化 Rb、AKT 和 S6，使 c-Myc/cyclin/Rb 和 PI3K/AKT 信号通路失活。在 c-Myc 扩增或高表达的异种移植瘤中，JQ1 诱导的肿瘤抑制作用高于低表达的异种移植瘤，表明其在预测中的潜在作用。总之，JQ1 通过靶向 c-Myc 可在体外和体内显著抑制 ESCC 肿瘤的生长。此外，c-Myc 扩增或高表达可能作为一种潜在的生物标志物，为 ESCC 提供一种有前途的治疗选择。
