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Tumor suppression by small molecule inhibitors of translation initiation
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 translat...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478463/ https://www.ncbi.nlm.nih.gov/pubmed/22935625 |
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author | Chen, Limo Aktas, Bertal H Wang, Yibo He, Xiaoying Sahoo, Rupam Zhang, Nancy Denoyelle, Severine Kabha, Eihab Yang, Hongwei Freedman, Revital Yefidoff Supko, Jeffrey G Chorev, Michael Wagner, Gerhard Halperin, Jose A |
author_facet | Chen, Limo Aktas, Bertal H Wang, Yibo He, Xiaoying Sahoo, Rupam Zhang, Nancy Denoyelle, Severine Kabha, Eihab Yang, Hongwei Freedman, Revital Yefidoff Supko, Jeffrey G Chorev, Michael Wagner, Gerhard Halperin, Jose A |
author_sort | Chen, Limo |
collection | PubMed |
description | 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-tRNA(i) 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. |
format | Online Article Text |
id | pubmed-3478463 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-34784632012-10-24 Tumor suppression by small molecule inhibitors of translation initiation Chen, Limo Aktas, Bertal H Wang, Yibo He, Xiaoying Sahoo, Rupam Zhang, Nancy Denoyelle, Severine Kabha, Eihab Yang, Hongwei Freedman, Revital Yefidoff Supko, Jeffrey G Chorev, Michael Wagner, Gerhard Halperin, Jose A Oncotarget Research Papers 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-tRNA(i) 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. Impact Journals LLC 2012-08-25 /pmc/articles/PMC3478463/ /pubmed/22935625 Text en Copyright: © 2012 Chen et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited |
spellingShingle | Research Papers Chen, Limo Aktas, Bertal H Wang, Yibo He, Xiaoying Sahoo, Rupam Zhang, Nancy Denoyelle, Severine Kabha, Eihab Yang, Hongwei Freedman, Revital Yefidoff Supko, Jeffrey G Chorev, Michael Wagner, Gerhard Halperin, Jose A Tumor suppression by small molecule inhibitors of translation initiation |
title | Tumor suppression by small molecule inhibitors of translation initiation |
title_full | Tumor suppression by small molecule inhibitors of translation initiation |
title_fullStr | Tumor suppression by small molecule inhibitors of translation initiation |
title_full_unstemmed | Tumor suppression by small molecule inhibitors of translation initiation |
title_short | Tumor suppression by small molecule inhibitors of translation initiation |
title_sort | tumor suppression by small molecule inhibitors of translation initiation |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478463/ https://www.ncbi.nlm.nih.gov/pubmed/22935625 |
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