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

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  • Author(s): Jin J;Jin J; Xiang W; Xiang W; Wu S; Wu S; Wang M; Wang M; Xiao M; Xiao M; Deng A; Deng A
  • Source:
    Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2019 Mar 19; Vol. 510 (4), pp. 580-586. Date of Electronic Publication: 2019 Feb 07.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0372516 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2104 (Electronic) Linking ISSN: 0006291X NLM ISO Abbreviation: Biochem Biophys Res Commun Subsets: MEDLINE
    • Publication Information:
      Publication: <2002- >: San Diego, CA : Elsevier
      Original Publication: New York, Academic Press.
    • Subject Terms:
      Antimetabolites/*therapeutic use ; Antineoplastic Agents/*therapeutic use ; Cisplatin/*therapeutic use ; Eukaryotic Initiation Factor-4E/*metabolism ; Ovarian Neoplasms/*drug therapy ; Ribavirin/*therapeutic use; Animals ; Antimetabolites/pharmacology ; Antineoplastic Agents/pharmacology ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Cell Line, Tumor ; Cisplatin/pharmacology ; Female ; Humans ; Mice, SCID ; Molecular Targeted Therapy ; Ovarian Neoplasms/metabolism ; Phosphorylation/drug effects ; Ribavirin/pharmacology ; Signal Transduction/drug effects
    • Abstract:
      The essential roles of eukaryotic translation initiation factor 4E (eIF4E) have been shown in various cancers, including ovarian cancer. In this work, we demonstrate that eIF4E 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 eIF4E and dependency to eIF4E 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 eIF4E expression varies among ovarian cancer. Additionally, ribavirin is a useful addition to ovarian cancer treatment, particularly to those with high dependency on eIF4E.
      (Copyright © 2019 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Akt/mTOR; Drug combination; Ovarian cancer; Ribavirin; eIF4E
    • Accession Number:
      0 (Antimetabolites)
      0 (Antineoplastic Agents)
      0 (Antiviral Agents)
      0 (Eukaryotic Initiation Factor-4E)
      49717AWG6K (Ribavirin)
      Q20Q21Q62J (Cisplatin)
    • Publication Date:
      Date Created: 20190212 Date Completed: 20191209 Latest Revision: 20191217
    • Publication Date:
      20231215
    • Accession Number:
      10.1016/j.bbrc.2019.01.117
    • Accession Number:
      30739792