Lin Shan, Shang Zhaoyang, Li Shuo, Gao Peng, Zhang Yi, Hou Shuaiheng, Qin Peng, Dong Ziming, Hu Tao, Chen Ping
Department of Basic Science of Oncology, College of Basic Medical Sciences, Zhengzhou University, Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan 450001, P.R. China.
Department of Immunotherapy, Henan Cancer Hospital and Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450008, P.R. China.
Oncol Lett. 2018 Feb;15(2):2583-2589. doi: 10.3892/ol.2017.7616. Epub 2017 Dec 14.
Inhibiting the protein neddylation pathway using the NEDD8-activating enzyme inhibitor MLN4924 represents an attractive anticancer strategy having been demonstrated to exhibit promising anticancer efficacy and with tolerable levels of toxicity; however, the mechanism by which MLN4924 inhibits cell proliferation in human esophageal squamous cell carcinoma (ESCC) cells requires further investigation. The present study revealed that MLN4924 treatment led to G cell cycle arrest and enhanced the protein stability of Wee1-like protein kinase and cyclin dependent protein kinase inhibitor 1A and B and p27. Furthermore, MLN4924 induced DNA damage and sensitized esophageal cancer cells to cisplatin by enhancing apoptosis. These findings extend the understanding of the function and mechanism of MLN4924 in ESCC and provide further evidence for the future development of neddylation inhibitors in clinical trials of esophageal cancer therapy, either alone or in combination.
使用NEDD8激活酶抑制剂MLN4924抑制蛋白质NEDD化途径是一种有吸引力的抗癌策略，已被证明具有良好的抗癌疗效且毒性水平可耐受；然而，MLN4924抑制人食管鳞状细胞癌（ESCC）细胞增殖的机制仍需进一步研究。本研究表明，MLN4924处理导致G期细胞周期停滞，并增强了Wee1样蛋白激酶、细胞周期蛋白依赖性蛋白激酶抑制剂1A和B以及p27的蛋白质稳定性。此外，MLN4924诱导DNA损伤，并通过增强凋亡使食管癌细胞对顺铂敏感。这些发现扩展了对MLN4924在ESCC中的功能和机制的理解，并为未来在食管癌治疗临床试验中单独或联合使用NEDD化抑制剂的开发提供了进一步的证据。
