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IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells

Internal ribosome entry site (IRES)-mediated translation is a specialized mode of protein synthesis which malignant cells depend on to survive adverse microenvironmental conditions. Our lab recently reported the identification of a group of compounds which selectively interfere with IRES-mediated tr...

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Autores principales: Vaklavas, Christos, Grizzle, William E., Choi, Hyoungsoo, Meng, Zheng, Zinn, Kurt R., Shrestha, Kedar, Blume, Scott W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Netherlands 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097113/
https://www.ncbi.nlm.nih.gov/pubmed/27460074
http://dx.doi.org/10.1007/s13277-016-5161-4
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author Vaklavas, Christos
Grizzle, William E.
Choi, Hyoungsoo
Meng, Zheng
Zinn, Kurt R.
Shrestha, Kedar
Blume, Scott W.
author_facet Vaklavas, Christos
Grizzle, William E.
Choi, Hyoungsoo
Meng, Zheng
Zinn, Kurt R.
Shrestha, Kedar
Blume, Scott W.
author_sort Vaklavas, Christos
collection PubMed
description Internal ribosome entry site (IRES)-mediated translation is a specialized mode of protein synthesis which malignant cells depend on to survive adverse microenvironmental conditions. Our lab recently reported the identification of a group of compounds which selectively interfere with IRES-mediated translation, completely blocking de novo IGF1R synthesis, and differentially modulating synthesis of the two c-Myc isoforms. Here, we examine the phenotypic consequences of sustained IRES inhibition in human triple-negative breast carcinoma and glioblastoma cells. A sudden loss of viability affects the entire tumor cell population after ∼72-h continuous exposure to the lead compound. The extraordinarily steep dose-response relationship (Hill-Slope coefficients −15 to −35) and extensive physical connections established between the cells indicate that the cells respond to IRES inhibition collectively as a population rather than as individual cells. Prior to death, the treated cells exhibit prominent features of terminal differentiation, with marked gains in cytoskeletal organization, planar polarity, and formation of tight junctions or neuronal processes. In addition to IGF1R and Myc, specific changes in connexin 43, BiP, CHOP, p21, and p27 also correlate with phenotypic outcome. This unusual mode of tumor cell death is absolutely dependent on exceeding a critical threshold in cell density, suggesting that a quorum-sensing mechanism may be operative. Death of putative tumor stem cells visualized in situ helps to explain the inability of tumor cells to recover and repopulate once the compound is removed. Together, these findings support the concept that IRES-mediated translation is of fundamental importance to maintenance of the undifferentiated phenotype and survival of undifferentiated malignant cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13277-016-5161-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-50971132016-11-21 IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells Vaklavas, Christos Grizzle, William E. Choi, Hyoungsoo Meng, Zheng Zinn, Kurt R. Shrestha, Kedar Blume, Scott W. Tumour Biol Original Article Internal ribosome entry site (IRES)-mediated translation is a specialized mode of protein synthesis which malignant cells depend on to survive adverse microenvironmental conditions. Our lab recently reported the identification of a group of compounds which selectively interfere with IRES-mediated translation, completely blocking de novo IGF1R synthesis, and differentially modulating synthesis of the two c-Myc isoforms. Here, we examine the phenotypic consequences of sustained IRES inhibition in human triple-negative breast carcinoma and glioblastoma cells. A sudden loss of viability affects the entire tumor cell population after ∼72-h continuous exposure to the lead compound. The extraordinarily steep dose-response relationship (Hill-Slope coefficients −15 to −35) and extensive physical connections established between the cells indicate that the cells respond to IRES inhibition collectively as a population rather than as individual cells. Prior to death, the treated cells exhibit prominent features of terminal differentiation, with marked gains in cytoskeletal organization, planar polarity, and formation of tight junctions or neuronal processes. In addition to IGF1R and Myc, specific changes in connexin 43, BiP, CHOP, p21, and p27 also correlate with phenotypic outcome. This unusual mode of tumor cell death is absolutely dependent on exceeding a critical threshold in cell density, suggesting that a quorum-sensing mechanism may be operative. Death of putative tumor stem cells visualized in situ helps to explain the inability of tumor cells to recover and repopulate once the compound is removed. Together, these findings support the concept that IRES-mediated translation is of fundamental importance to maintenance of the undifferentiated phenotype and survival of undifferentiated malignant cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13277-016-5161-4) contains supplementary material, which is available to authorized users. Springer Netherlands 2016-07-26 /pmc/articles/PMC5097113/ /pubmed/27460074 http://dx.doi.org/10.1007/s13277-016-5161-4 Text en © The Author(s) 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Vaklavas, Christos
Grizzle, William E.
Choi, Hyoungsoo
Meng, Zheng
Zinn, Kurt R.
Shrestha, Kedar
Blume, Scott W.
IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells
title IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells
title_full IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells
title_fullStr IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells
title_full_unstemmed IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells
title_short IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells
title_sort ires inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097113/
https://www.ncbi.nlm.nih.gov/pubmed/27460074
http://dx.doi.org/10.1007/s13277-016-5161-4
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