a State Key Laboratory of Medical Molecular Biology , Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College , Beijing China.
c Department of Medical Oncology , Chifeng Municipal Hospital , Chifeng China.
Cancer Biol Ther. 2018;19(12):1128-1138. doi: 10.1080/15384047.2018.1480293. Epub 2018 Sep 27.
Chemotherapy resistance represents a major issue associated with gastric cancer (GC) treatment, and arises through multiple mechanisms, including modulation of the cell-cycle check point. Several ubiquitin kinases, including RING finger protein 138 (RNF138), have been reported to mediate the G2/M phase arrest. In this study, we investigated the role of RNF138 in the development of cisplatin resistance of two GC cell lines. We show that RNF138 levels are higher in cisplatin-resistant cell lines, compared with cisplatin-sensitive cells, and RNF138 expression was elevated during drug withdrawal following the cisplatin treatment. Using gene overexpression and silencing, we analyzed the impact of altering RNF138 level on GC cell viability, apoptosis, and cell cycle phenotypes in two isogenic cisplatin-sensitive and resistant cell lines. We show that RNF138 overexpression increased GC cell viability, decreased apoptosis and delayed cell cycle progression in the cisplatin-sensitive GC cells. Conversely, RNF138 silencing produced opposite phenotypes in the cisplatin-resistant cells. Moreover, RNF138-dependent phosphorylation of Chk1 was seen in GC cells, indicating a novel connection between cisplatin-induced DNA damage and apoptosis. Collectively, these data suggest that RNF138 modulates the cisplatin resistance in the GC cells, thus serving as a potential drug target to challenge chemotherapy failure. In addition, RNF138 can also be used as a marker to monitor the development of cisplatin resistance in GC treatment.
化疗耐药性是与胃癌（GC）治疗相关的主要问题，它通过多种机制产生，包括细胞周期检查点的调节。几种泛素激酶，包括环指蛋白 138（RNF138），已被报道介导 G2/M 期阻滞。在这项研究中，我们研究了 RNF138 在两种 GC 细胞系中顺铂耐药性发展中的作用。我们发现，与顺铂敏感细胞相比，顺铂耐药细胞系中的 RNF138 水平更高，并且在顺铂治疗后药物撤出期间 RNF138 表达上调。通过基因过表达和沉默，我们分析了改变 RNF138 水平对两种同源顺铂敏感和耐药细胞系中 GC 细胞活力、凋亡和细胞周期表型的影响。我们发现，RNF138 过表达增加了 GC 细胞活力，减少了顺铂敏感 GC 细胞中的凋亡并延迟了细胞周期进程。相反，RNF138 沉默在顺铂耐药细胞中产生了相反的表型。此外，在 GC 细胞中观察到 RNF138 依赖性 Chk1 磷酸化，表明顺铂诱导的 DNA 损伤和凋亡之间存在新的联系。总之，这些数据表明 RNF138 调节 GC 细胞中的顺铂耐药性，因此可作为挑战化疗失败的潜在药物靶点。此外，RNF138 还可以用作监测 GC 治疗中顺铂耐药性发展的标志物。
