Targeting eIF4E signaling with ribavirin as a sensitizing strategy for ovarian cancer

摘要

The essential roles of eukaryotic translation initiation factor 4E (elF4E) have been shown in various cancers, including ovarian cancer. In this work, we demonstrate that elF4E inhibition in ovarian cancer can be achieved by ribavirin, a FDA-approved antiviral drug. We show that ribavirin at clinically relevant doses significantly inhibits growth and survival in multiple ovarian cancer cell lines, regardless of morphological and molecular subtypes. Mechanistically, ribavirin suppresses Akt/mTOR and eIF4E/p70S6K signaling pathways in ovarian cancer cells. We confirm that eIF4E is the critical molecular target of ribavirin, and furthermore that this is dependent on phosphorylation at S209. Notably, using both in vitro cell culture system and in vivo xenograft mouse model, we show that the combination of ribavirin with cisplatin (standard of care for patients with ovarian cancer) results in significantly greater efficacy than cisplatin alone in ovarian cancer. Interestingly, the sensitivity to ribavirin varies among a panel of ovarian cancer cell lines, mostly likely due to their differential expression level of elF4E and dependency to elF4E inhibition. The differential expression level is further observed in ovarian cancer tissues, with the higher level of eIF4E in the majority of ovarian cancer tissues compared to normal ovary tissues. Our work suggests that elF4E expression varies among ovarian cancer. Additionally, ribavirin is a useful addition to ovarian cancer treatment, particularly to those with high dependency on elF4E. (C) 2019 Elsevier Inc. All rights reserved.