Targeting eIF4E inhibits growth, survival and angiogenesis in retinoblastoma and enhances efficacy of chemotherapy

Abstract

Although the eukaryotic translation initiation factor 4E (eIF4E) has been shown to be critically involved in the transformation and progression of various tumors, little is known about the role of eIF4E in retinoblastoma. In this work, we report that ribavirin, a pharmacologic inhibitor of eIF4E function, effectively targets retinoblastoma and angiogenesis. Ribavirin treatment dose-dependently blocked the growth and stimulated apoptosis in various retinoblastoma cell lines, with IC₅₀ values that are within the clinically achievable range. Ribavirin also significantly inhibited angiogenesis via disrupting capillary network formation and suppressing VEGF-induced migration, proliferation and survival of human retinal endothelial cells. In addition, ribavirin significantly augments chemotherapy agent's inhibitory effects in retinoblastoma in vitro and in vivo. Mechanistically, ribavirin inhibited eIF4E function in retinoblastoma cells as shown by the decreased protein levels of Cyclin D1, c-Myc and VEGF without affecting their mRNA expression. Overexpression of the wildtype and phosphormimetic but not the nonphosphorylatable form of eIF4E significantly abolished the inhibitory effects of ribavirin, further demonstrating eIF4E as the target of ribavirin. Genetic knockdown of eIF4E using two independent siRNAs mirrored ribavirin's effects, confirming the role of eIF4E in retinoblastoma growth, survival and response to chemotherapy. Our findings provide a preclinical rationale to explore ribavirin as a strategy to treat retinoblastoma and highlight the therapeutic value of targeting eIF4E in retinoblastoma.

Keywords: Angiogenesis; Retinoblastoma; Ribavirin; eIF4E.