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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 pr...

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Autores principales: Cao, Yang, He, Ying, Yang, Litao, Luan, Zhou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709814/
https://www.ncbi.nlm.nih.gov/pubmed/33416145
http://dx.doi.org/10.3892/or.2020.7856
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author Cao, Yang
He, Ying
Yang, Litao
Luan, Zhou
author_facet Cao, Yang
He, Ying
Yang, Litao
Luan, Zhou
author_sort Cao, Yang
collection PubMed
description 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.
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spelling pubmed-77098142020-12-03 Targeting eIF4A using rocaglate CR-1-31B sensitizes gallbladder cancer cells to TRAIL-mediated apoptosis through the translational downregulation of c-FLIP Cao, Yang He, Ying Yang, Litao Luan, Zhou Oncol Rep Articles 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. D.A. Spandidos 2021-01 2020-11-17 /pmc/articles/PMC7709814/ /pubmed/33416145 http://dx.doi.org/10.3892/or.2020.7856 Text en Copyright: © Cao et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Cao, Yang
He, Ying
Yang, Litao
Luan, Zhou
Targeting eIF4A using rocaglate CR-1-31B sensitizes gallbladder cancer cells to TRAIL-mediated apoptosis through the translational downregulation of c-FLIP
title Targeting eIF4A using rocaglate CR-1-31B sensitizes gallbladder cancer cells to TRAIL-mediated apoptosis through the translational downregulation of c-FLIP
title_full Targeting eIF4A using rocaglate CR-1-31B sensitizes gallbladder cancer cells to TRAIL-mediated apoptosis through the translational downregulation of c-FLIP
title_fullStr Targeting eIF4A using rocaglate CR-1-31B sensitizes gallbladder cancer cells to TRAIL-mediated apoptosis through the translational downregulation of c-FLIP
title_full_unstemmed Targeting eIF4A using rocaglate CR-1-31B sensitizes gallbladder cancer cells to TRAIL-mediated apoptosis through the translational downregulation of c-FLIP
title_short Targeting eIF4A using rocaglate CR-1-31B sensitizes gallbladder cancer cells to TRAIL-mediated apoptosis through the translational downregulation of c-FLIP
title_sort targeting eif4a using rocaglate cr-1-31b sensitizes gallbladder cancer cells to trail-mediated apoptosis through the translational downregulation of c-flip
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709814/
https://www.ncbi.nlm.nih.gov/pubmed/33416145
http://dx.doi.org/10.3892/or.2020.7856
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