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Polyamine-modified naphthalimide derivative 9C inhibits colorectal cancer through ROS-mediated ER stress, migration
Xiaojuan Xu1, Chaochao Ge2, Senzhen Wang3
1School of Pharmacy, Henan University, Kaifeng 475004, Henan, China.
Abstract:
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.
Insights
Naphthalimide derivative 9C triggers endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in colorectal cancer cells, inhibiting growth, migration, and invasion. This suggests a therapeutic strategy targeting ROS-mediated ER stress.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Targeting endoplasmic reticulum (ER) stress shows therapeutic promise in cancer treatment.
- Naphthalimides possess anti-cancer activities, but their impact on ER stress is understudied.
Purpose of the Study:
- To investigate the effects of naphthalimide derivative 9C on ER stress signaling in colorectal cancer (CRC).
- To elucidate the role of reactive oxygen species (ROS) and autophagy in 9C's anti-cancer mechanisms.
Main Methods:
- RNA-sequencing analysis to identify 9C-induced cellular responses.
- Utilized ER stress and autophagy inhibitors (salubrinal, 3-methyladenine) to assess their impact on cell growth.
- Investigated the role of ROS by using N-acetyl-L-cysteine (NAC) and measured key protein expressions.
Main Results:
- 9C triggered ER stress, activating death receptor signaling and autophagy in CRC cells.
- ER stress and autophagy inhibition partially reversed 9C's anti-proliferative effects.
- 9C's anti-cancer activity was dependent on reactive oxygen species (ROS) production.
- 9C inhibited CRC cell migration and invasion, effects attenuated by ROS removal.
Conclusions:
- Naphthalimide 9C exerts anti-cancer effects in CRC by inducing ROS-mediated ER stress.
- The observed inhibition of cell growth, migration, and invasion is linked to ROS-dependent ER stress pathways.
- Targeting ROS-mediated ER stress represents a potential therapeutic strategy for colorectal cancer using naphthalimides.
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