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Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway

The selective degradation of target proteins with small molecules is a novel approach to the treatment of various diseases, including cancer. We have developed a protein knockdown system with a series of hybrid small compounds that induce the selective degradation of target proteins via the ubiquiti...

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Autores principales: Ohoka, N, Nagai, K, Hattori, T, Okuhira, K, Shibata, N, Cho, N, Naito, M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260729/
https://www.ncbi.nlm.nih.gov/pubmed/25375378
http://dx.doi.org/10.1038/cddis.2014.471
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author Ohoka, N
Nagai, K
Hattori, T
Okuhira, K
Shibata, N
Cho, N
Naito, M
author_facet Ohoka, N
Nagai, K
Hattori, T
Okuhira, K
Shibata, N
Cho, N
Naito, M
author_sort Ohoka, N
collection PubMed
description The selective degradation of target proteins with small molecules is a novel approach to the treatment of various diseases, including cancer. We have developed a protein knockdown system with a series of hybrid small compounds that induce the selective degradation of target proteins via the ubiquitin–proteasome pathway. In this study, we designed and synthesized novel small molecules called SNIPER(TACC3)s, which target the spindle regulatory protein transforming acidic coiled-coil-3 (TACC3). SNIPER(TACC3)s induce poly-ubiquitylation and proteasomal degradation of TACC3 and reduce the TACC3 protein level in cells. Mechanistic analysis indicated that the ubiquitin ligase APC/C(CDH1) mediates the SNIPER(TACC3)-induced degradation of TACC3. Intriguingly, SNIPER(TACC3) selectively induced cell death in cancer cells expressing a larger amount of TACC3 protein than normal cells. These results suggest that protein knockdown of TACC3 by SNIPER(TACC3) is a potential strategy for treating cancers overexpressing the TACC3 protein.
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spelling pubmed-42607292014-12-15 Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway Ohoka, N Nagai, K Hattori, T Okuhira, K Shibata, N Cho, N Naito, M Cell Death Dis Original Article The selective degradation of target proteins with small molecules is a novel approach to the treatment of various diseases, including cancer. We have developed a protein knockdown system with a series of hybrid small compounds that induce the selective degradation of target proteins via the ubiquitin–proteasome pathway. In this study, we designed and synthesized novel small molecules called SNIPER(TACC3)s, which target the spindle regulatory protein transforming acidic coiled-coil-3 (TACC3). SNIPER(TACC3)s induce poly-ubiquitylation and proteasomal degradation of TACC3 and reduce the TACC3 protein level in cells. Mechanistic analysis indicated that the ubiquitin ligase APC/C(CDH1) mediates the SNIPER(TACC3)-induced degradation of TACC3. Intriguingly, SNIPER(TACC3) selectively induced cell death in cancer cells expressing a larger amount of TACC3 protein than normal cells. These results suggest that protein knockdown of TACC3 by SNIPER(TACC3) is a potential strategy for treating cancers overexpressing the TACC3 protein. Nature Publishing Group 2014-11 2014-11-06 /pmc/articles/PMC4260729/ /pubmed/25375378 http://dx.doi.org/10.1038/cddis.2014.471 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0
spellingShingle Original Article
Ohoka, N
Nagai, K
Hattori, T
Okuhira, K
Shibata, N
Cho, N
Naito, M
Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway
title Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway
title_full Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway
title_fullStr Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway
title_full_unstemmed Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway
title_short Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway
title_sort cancer cell death induced by novel small molecules degrading the tacc3 protein via the ubiquitin–proteasome pathway
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260729/
https://www.ncbi.nlm.nih.gov/pubmed/25375378
http://dx.doi.org/10.1038/cddis.2014.471
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