Article Abstract

Genetic and pharmacological inhibition of eIF4E effectively targets esophageal cancer cells and augments 5-FU’s efficacy

Authors: Jindan Kai, Yiqiao Wang, Fei Xiong, Sheng Wang

Abstract

Background: Aberrant activation of eIF4E is critically involved in the progression and chemoresistance of various cancers. Elevated expression of eIF4E has also been documented in human cancerous esophageal tissues. However, the role of eIF4E in esophageal cancer is unclear.
Methods: We analysed the levels of eIF4E expression and eIF4E function in a number of normal and cancerous esophageal cancer cell lines, and studied its underlying mechanism.
Results: We observed that eIF4E expression varies in different esophageal cancer cell lines but was significantly elevated in all tested esophageal cell lines as compared to the control cell lines. We demonstrated that eIF4E inhibition via genetic and pharmacological approaches inhibits cancer cell growth and survival. This inhibition also augments 5-flurouracil’s (5-FU’s) efficacy as demonstrated with both the in vitro esophageal cancer culture system and our in vivo xenograft mouse model. Of note, the sensitivity of esophageal cancer cells to ribavirin or eIF4E knockdown correlates well with the expression levels of eIF4E, demonstrating that esophageal cells with higher eIF4E expression are more sensitive to eIF4E inhibition. We further confirmed that the mechanism of action of ribavirin on esophageal cancer cells was through suppressing the Akt/mTOR/eIF4E and eIF4E-regulated pathways.
Conclusions: To our knowledge, our work is the first to demonstrate the multiple roles of eIF4E in esophageal cancer. eIF4E was shown to promote cancer cell growth and survival, and protected the cells from chemotherapy. Our work also demonstrated that ribavirin is an attractive candidate for the treatment of esophageal cancer.