Oncotarget

Research Papers:

Tumor suppression by small molecule inhibitors 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 and Jose A. Halperin

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Oncotarget. 2012; 3:869-881. https://doi.org/10.18632/oncotarget.598

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Abstract

Limo Chen1,*, Bertal H Aktas1,2,*, Yibo Wang1, Xiaoying He1,3, Rupam Sahoo1, Nancy Zhang1, Severine Denoyelle1, Eihab Kabha1, Hongwei Yang1, Revital Yefidoff Freedman1, Jeffrey G Supko1,3, Michael Chorev1,2, Gerhard Wagner1, and Jose A Halperin1,2

1 Harvard Medical School

2 Brigham and Women’s Hospital

3 Massachusetts General Hospital

* These authors are equal contributors

Correspondence:

Jose A. Halperin , email:

Keywords: Translation, eIF4F, eIF4E, ternary complex, eIF2

Received: August 09, 2012, Accepted: August 24, 2012, Published: August 25, 2012

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.


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