Mi Wunan, Wang Chuyue, Luo Guang, Li Jiehan, Zhang Yizheng, Jiang Meimei, Zhang Chuchu, Liu Nannan, Jiang Xinxiu, Yang Ge, Zhang Lingling, Zhang Ge, Zhang Yingjie, Fu Yang
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.
College of Biology, Hunan University, 410082, Changsha, China.
Cell Death Discov. 2021 Dec 4;7(1):375. doi: 10.1038/s41420-021-00677-9.
In recent years, many studies have shown that autophagy plays a vital role in the resistance of tumor chemotherapy. However, the interaction between autophagy and cell death has not yet been clarified. In this study, a new specific ERK inhibitor CC90003 was found to suppress colorectal cancer growth by inducing cell death both in vitro and in vivo. Studies have confirmed that higher concentrations of ROS leads to autophagy or cell death. In this research, the role of CC90003-induced ROS was verified. But after inhibiting ROS by two kinds of ROS inhibitors NAC and SFN, the autophagy induced by CC90003 decreased, while cell death strengthened. In parallel, protective autophagy was also induced, while in a p53-dependent manner. After silencing p53 or using the p53 inhibitor PFTα, the autophagy induced by CC90003 was weakened and the rate of cell death increases. Therefore, we confirmed that CC90003 could induce autophagy by activating ROS/p53. Furthermore, in the xenograft mouse model, the effect was obtained remarkably in the combinational treatment group of CC90003 plus CQ, comparing with that of the single treatment groups. In a word, our results demonstrated that targeting ERK leads to cell death and p53/ROS-dependent protective autophagy simultaneously in colorectal cancer, which offers new potential targets for clinical therapy.
近年来，许多研究表明自噬在肿瘤化疗耐药中起着至关重要的作用。然而，自噬与细胞死亡之间的相互作用尚未阐明。在本研究中，发现一种新的特异性ERK抑制剂CC90003在体外和体内均可通过诱导细胞死亡来抑制结直肠癌的生长。研究证实，较高浓度的活性氧（ROS）会导致自噬或细胞死亡。在本研究中，验证了CC90003诱导ROS的作用。但是在用两种ROS抑制剂NAC和SFN抑制ROS后，CC90003诱导的自噬减少，而细胞死亡增强。同时，还诱导了保护性自噬，且呈p53依赖性。在沉默p53或使用p53抑制剂PFTα后，CC90003诱导的自噬减弱，细胞死亡率增加。因此，我们证实CC90003可通过激活ROS/p53诱导自噬。此外，在异种移植小鼠模型中，与单一治疗组相比，CC90003加CQ的联合治疗组效果显著。总之，我们的结果表明，靶向ERK可在结直肠癌中同时导致细胞死亡和p53/ROS依赖性保护性自噬，这为临床治疗提供了新的潜在靶点。
