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New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells
Serrated adenocarcinoma (SAC) is more invasive, has worse outcomes than conventional colorectal carcinoma (CRC), and is characterized by frequent resistance to anti-epidermal growth factor receptor (EGFR) and overexpression of fascin1, a key protein in actin bundling that plays a causative role in t...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062870/ https://www.ncbi.nlm.nih.gov/pubmed/32080340 http://dx.doi.org/10.1038/s12276-020-0389-x |
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author | Alburquerque-González, Begoña Bernabé-García, Manuel Montoro-García, Silvia Bernabé-García, Ángel Rodrigues, Priscila Campioni Ruiz Sanz, Javier López-Calderón, Fernando F. Luque, Irene Nicolas, Francisco José Cayuela, María Luisa Salo, Tuula Pérez-Sánchez, Horacio Conesa-Zamora, Pablo |
author_facet | Alburquerque-González, Begoña Bernabé-García, Manuel Montoro-García, Silvia Bernabé-García, Ángel Rodrigues, Priscila Campioni Ruiz Sanz, Javier López-Calderón, Fernando F. Luque, Irene Nicolas, Francisco José Cayuela, María Luisa Salo, Tuula Pérez-Sánchez, Horacio Conesa-Zamora, Pablo |
author_sort | Alburquerque-González, Begoña |
collection | PubMed |
description | Serrated adenocarcinoma (SAC) is more invasive, has worse outcomes than conventional colorectal carcinoma (CRC), and is characterized by frequent resistance to anti-epidermal growth factor receptor (EGFR) and overexpression of fascin1, a key protein in actin bundling that plays a causative role in tumor invasion and is overexpressed in different cancer types with poor prognosis. In silico screening of 9591 compounds, including 2037 approved by the Food and Drug Administration (FDA), was performed, and selected compounds were analyzed for their fascin1 binding affinity by differential scanning fluorescence. The results were compared with migrastatin as a typical fascin1 inhibitor. In silico screening and differential scanning fluorescence yielded the FDA-approved antidepressant imipramine as the most evident potential fascin1 blocker. Biophysical and different in vitro actin-bundling assays confirm this activity. Subsequent assays investigating lamellipodia formation and migration and invasion of colorectal cancer cells in vitro using 3D human tissue demonstrated anti-fascin1 and anti-invasive activities of imipramine. Furthermore, expression profiling suggests the activity of imipramine on the actin cytoskeleton. Moreover, in vivo studies using a zebrafish invasion model showed that imipramine is tolerated, its anti-invasive and antimetastatic activities are dose-dependent, and it is associated with both constitutive and induced fascin1 expression. This is the first study that demonstrates an antitumoral role of imipramine as a fascin1 inhibitor and constitutes a foundation for a molecular targeted therapy for SAC and other fascin1-overexpressing tumors. |
format | Online Article Text |
id | pubmed-7062870 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70628702020-03-18 New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells Alburquerque-González, Begoña Bernabé-García, Manuel Montoro-García, Silvia Bernabé-García, Ángel Rodrigues, Priscila Campioni Ruiz Sanz, Javier López-Calderón, Fernando F. Luque, Irene Nicolas, Francisco José Cayuela, María Luisa Salo, Tuula Pérez-Sánchez, Horacio Conesa-Zamora, Pablo Exp Mol Med Article Serrated adenocarcinoma (SAC) is more invasive, has worse outcomes than conventional colorectal carcinoma (CRC), and is characterized by frequent resistance to anti-epidermal growth factor receptor (EGFR) and overexpression of fascin1, a key protein in actin bundling that plays a causative role in tumor invasion and is overexpressed in different cancer types with poor prognosis. In silico screening of 9591 compounds, including 2037 approved by the Food and Drug Administration (FDA), was performed, and selected compounds were analyzed for their fascin1 binding affinity by differential scanning fluorescence. The results were compared with migrastatin as a typical fascin1 inhibitor. In silico screening and differential scanning fluorescence yielded the FDA-approved antidepressant imipramine as the most evident potential fascin1 blocker. Biophysical and different in vitro actin-bundling assays confirm this activity. Subsequent assays investigating lamellipodia formation and migration and invasion of colorectal cancer cells in vitro using 3D human tissue demonstrated anti-fascin1 and anti-invasive activities of imipramine. Furthermore, expression profiling suggests the activity of imipramine on the actin cytoskeleton. Moreover, in vivo studies using a zebrafish invasion model showed that imipramine is tolerated, its anti-invasive and antimetastatic activities are dose-dependent, and it is associated with both constitutive and induced fascin1 expression. This is the first study that demonstrates an antitumoral role of imipramine as a fascin1 inhibitor and constitutes a foundation for a molecular targeted therapy for SAC and other fascin1-overexpressing tumors. Nature Publishing Group UK 2020-02-20 /pmc/articles/PMC7062870/ /pubmed/32080340 http://dx.doi.org/10.1038/s12276-020-0389-x Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Alburquerque-González, Begoña Bernabé-García, Manuel Montoro-García, Silvia Bernabé-García, Ángel Rodrigues, Priscila Campioni Ruiz Sanz, Javier López-Calderón, Fernando F. Luque, Irene Nicolas, Francisco José Cayuela, María Luisa Salo, Tuula Pérez-Sánchez, Horacio Conesa-Zamora, Pablo New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells |
title | New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells |
title_full | New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells |
title_fullStr | New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells |
title_full_unstemmed | New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells |
title_short | New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells |
title_sort | new role of the antidepressant imipramine as a fascin1 inhibitor in colorectal cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062870/ https://www.ncbi.nlm.nih.gov/pubmed/32080340 http://dx.doi.org/10.1038/s12276-020-0389-x |
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