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Inhibition of eIF4E cooperates with chemotherapy and immunotherapy in renal cell carcinoma

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Abstract

Purpose

Although overexpression of the eukaryotic translation initiation factor 4E (eIF4E) is detected in patients with renal cell carcinoma (RCC) and associated with poor prognosis, the possible roles of eIF4E in RCC have not been revealed.

Methods

The effects of eIF4E inhibition on cell growth, migration, survival, chemo-/immunotherapy and eIF4E pathways via pharmacological inhibitor and genetic siRNA knockdown were analyzed in RCC cells.

Results

In this work, we demonstrate that eIF4E is critically involved in multiple biological functions of RCC. We firstly inhibited eIF4E activity by ribavirin in two cell lines (Caki-1 and ACHN) representing RCC metastasis models. We demonstrated that ribavirin inhibited proliferation and migration and induced apoptosis in RCC in a dose-dependent manner. We further confirmed that the inhibitory effects of ribavirin were attributed to its ability in inhibiting eIF4E-regulated protein translation and activity. eIF4E inhibition using siRNA knockdown mimicked ribavirin’s effector in RCC cells. Importantly, eIF4E inhibition by both ribavirin and siRNA knockdown significantly sensitized RCC response to chemo- and immunotherapeutic agents in vitro as well as in vivo.

Conclusions

Our findings clearly demonstrate the roles of eIF4E in RCC growth, survival, metastasis and resistance. Ribavirin is an antiviral drug, and its clinical efficacy is currently being investigated in the treatment of various cancers. Our findings support and provide a preclinical evidence for clinical trial for the combination of ribavirin with chemo-/immunotherapy in RCC.

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Acknowledgements

This work was supported by a research grant provided by Xiangyang Central Hospital (2012050689).

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Authors and Affiliations

  1. Department of Urology, Xiangyang Central Hospital, Hospital Affiliated to Hubei University of Arts and Science, 39 Jingzhou Street, Xiangyang, 441021, Hubei, People’s Republic of China

    J. Cao, X. Sun, X. Zhang & D. Chen

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  1. J. Cao
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  2. X. Sun
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  3. X. Zhang
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  4. D. Chen
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Contributions

JC designed the experiments, performed the experiments, interpreted the data and wrote the manuscript. XS and XJZ performed the experiments and analyzed the data. DHC interpreted the data and revised the manuscript. All authors approved the final manuscripts.

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Correspondence to D. Chen.

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The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

All applicable international, national and/or institutional guidelines for the care and use of animals were followed. The animal experiments were approved by the Institutional Animal Care and Use Committee of Xiangyang Central Hospital.

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Cao, J., Sun, X., Zhang, X. et al. Inhibition of eIF4E cooperates with chemotherapy and immunotherapy in renal cell carcinoma. Clin Transl Oncol 20, 761–767 (2018). https://doi.org/10.1007/s12094-017-1786-z

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  • DOI: https://doi.org/10.1007/s12094-017-1786-z

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