Xu Xiaojuan, Ge Chaochao, Wang Senzhen, Gao Lei, Wang Chaojie, Dai Fujun, Wang Yuxia, Xie Songqiang
School of Pharmacy, Henan University, Kaifeng 475004, Henan, China.
Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng 475004, Henan, China; School of Pharmacy, Heze University, Heze 274015, Shandong, China.
Toxicol In Vitro. 2025 Mar;103:105974. doi: 10.1016/j.tiv.2024.105974. Epub 2024 Nov 23.
Mounting evidence over the past decades has demonstrated the therapeutic potential of targeting endoplasmic reticulum (ER) stress signaling in cancer. Naphthalimdes exert their anti-cancer activities in a variety of ways. However, the effects of naphthalimides on ER stress are rarely reported. In this study, based on RNA-sequencing analysis, we observed that 9C, a naphthalimide derivative, could trigger ER stress to activate death receptor signaling and autophagy. Pretreatment of ER stress inhibitor, such as salubrinal, and autophagy inhibitor, such as 3-methyladenine (3-MA), partially reversed 9C-induced inhibition of cell growth. Furthermore, our results unveiled a reactive oxygen species (ROS)-dependent inhibitory effect of 9C. In addition, 9C inhibited colorectal cancer (CRC) cells migration and invasion. Removal of ROS using N-acetyl-L-cysteine (NAC) attenuated the expression of ATF4, CHOP, death receptors, E-cadherin, and the apoptosis and autophagy related proteins. Taken together, our results suggested that ROS-mediated ER stress, migration, and invasion is responsible for the therapeutic potential of naphthalimides including 9C in CRC.
在过去几十年中，越来越多的证据表明，针对内质网（ER）应激信号传导在癌症治疗中具有潜力。萘二甲酰亚胺以多种方式发挥其抗癌活性。然而，萘二甲酰亚胺对内质网应激的影响鲜有报道。在本研究中，基于RNA测序分析，我们观察到萘二甲酰亚胺衍生物9C可引发内质网应激以激活死亡受体信号传导和自噬。内质网应激抑制剂（如salubrinal）和自噬抑制剂（如3-甲基腺嘌呤（3-MA））的预处理部分逆转了9C诱导的细胞生长抑制。此外，我们的结果揭示了9C的活性氧（ROS）依赖性抑制作用。此外，9C抑制结直肠癌（CRC）细胞的迁移和侵袭。使用N-乙酰-L-半胱氨酸（NAC）去除ROS可减弱ATF4、CHOP、死亡受体、E-钙粘蛋白以及凋亡和自噬相关蛋白的表达。综上所述，我们的结果表明，ROS介导的内质网应激、迁移和侵袭是萘二甲酰亚胺（包括9C）在结直肠癌中具有治疗潜力的原因。
