Targeting eIF4A using rocaglate CR‑1‑31B sensitizes gallbladder cancer cells to TRAIL‑mediated apoptosis through the translational downregulation of c‑FLIP.

Induction of the apoptosis of tumor cells is a promising therapeutic approach for the treatment of cancer. Tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) is a novel type of anticancer drug. However, gallbladder cancer cells (GBC) exhibit strong resistance to TRAIL. The aim of the present study was to assess the effect of rocaglate CR‑1‑31B (CR‑31), an inhibitor of eukaryotic translation initiation factor 4A (eIF4A), on the sensitization of cells to TRAIL‑induced apoptosis in TRAIL‑resistant GBC. eIF4A was highly abundant in GBC tissues and cell lines (GBC‑SD and SGC‑996). GBC cells were treated using TRAIL and/or CR‑31 and then apoptosis and TRAIL signaling were detected in vitro. CR‑31 enhanced the sensitivity of TRAIL‑resistant GBC cells, due to the CR‑31‑mediated eIF4A translational downregulation of c‑FLIP and the subsequent activation of the caspase cascade. Furthermore, GBC‑SD tumor xenografts models were established and the effects of CR‑31 in vivo were assessed. CR‑31 significantly reduced the growth and initiated the apoptosis of tumor cells, suggesting that CR‑31 also increased sensitivity in vivo. Taken together, the results of the present study show that CR‑31 treatment countered the resistance to TRAIL in GBC cells in vitro and in vivo. Therefore, eIF4A may serve as a novel therapeutic target and its combination with TRAIL‑CR‑31 as a therapy may serve as a novel strategy for GBC treatment.