Tumor suppression by small molecule inhibitorss of translation initiation

Limo Chen, Bertal H. Aktas, Yibo Wang, Xiaoying He, Rupam Sahoo, Nancy Zhang, Severine Denoyelle, Eihab Kabha, Hongwei Yang, Revital Yefidoff Freedman, Jeffrey G. Supko, Michael Chorev, Gerhard Wagner, Jose A. Halperin

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Translation initiation factors are over-expressed and/or activated in many human cancers and may contribute to their genesis and/or progression. Removal of physiologic restraints on translation initiation causes malignant transformation. Conversely, restoration of physiological restrains on translation initiation reverts malignant phenotypes. Here, we extensively characterize the anti-cancer activity of two small molecule inhibitors of translation initiation: #1181, which targets the eIF2 GTP Met-tRNAi ternary complex, and 4EGI-1, which targets the eIF4F complex. In vitro, both molecules inhibit translation initiation, abrogate preferentially translation of mRNAs coding for oncogenic proteins, and inhibit proliferation of human cancer cells. In vivo, both #1181 and 4EGI-1 strongly inhibit growth of human breast and melanoma cancer xenografts without any apparent macroscopic- or microscopic-toxicity. Mechanistically, #1181 phosphorylates eIF2α while 4EGI-1 disrupts eIF4G/ eIF4E interaction in the tumors excised from mice treated with these agents. These data indicate that inhibition of translation initiation is a new paradigm in cancer therapy.

Original languageEnglish
Pages (from-to)869-881
Number of pages13
JournalOncotarget
Volume3
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

Funding

FundersFunder number
National Cancer InstituteR01CA152312

    Keywords

    • EIF2
    • EIF4F
    • EIF4e
    • Ternary complex
    • Translation

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