Targeting ERK induced cell death and p53/ROS-dependent protective autophagy in colorectal cancer.
Targeting ERK induced cell death and p53/ROS-dependent protective autophagy in colorectal cancer.
复制标题
靶向结直肠癌中 ERK 诱导的细胞死亡和 p53/ROS 依赖性保护性自噬
DOI：
10.1038/s41420-021-00677-9
复制
发表时间：
2021-12-04
影响因子：
7
通讯作者：
Fu Y
中科院分区：
文献类型：
--
作者：
Mi W;Wang C;Luo G;Li J;Zhang Y;Jiang M;Zhang C;Liu N;Jiang X;Yang G;Zhang L;Zhang G;Zhang Y;Fu Y
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。在这项研究中，发现一种新的特异性细胞外调节蛋白激酶（ERK）抑制剂CC90003通过在体外和体内诱导细胞死亡来抑制结直肠癌的生长。研究已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诱导的ROS的作用。但是在使用两种ROS抑制剂N - 乙酰半胱氨酸（NAC）和萝卜硫素（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，且是以p53依赖的方式。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加氯喹（CQ）联合治疗组效果显著。总之，我们的研究结果表明，在结直肠癌中，靶向ERK可同时导致细胞死亡以及p53/ROS依赖的保护性自噬，这为临床治疗提供了新的潜在靶点。
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.
登录
查看更多内容
影响因子：
5.2
作者：
Kaewpiboon, Chutima;Surapinit, Serm;Chung, Young-hwa
通讯作者：
Chung, Young-hwa
影响因子：
13.3
作者：
Kaminskyy, Vitaliy O.;Piskunova, Tatiana;Zhivotovsky, Boris
通讯作者：
Zhivotovsky, Boris
阻断 AMPK/ULK1 依赖性自噬促进细胞凋亡并抑制结肠癌生长
影响因子：
5.8
作者：
Liu, Jing;Long, Shuaiyu;Zhang, Yingjie
通讯作者：
Zhang, Yingjie
影响因子：
13.3
作者：
Jing, Kaipeng;Song, Kyoung-Sub;Lim, Kyu
通讯作者：
Lim, Kyu
影响因子：
10.3
作者：
O'Connell, JB;Maggard, MA;Ko, CY
通讯作者：
Ko, CY