Polyamine-modified naphthalimide derivative 9C inhibits colorectal cancer through ROS-mediated ER stress, migration and invasion.

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.