University of Oulu

Alburquerque-González, B., Bernabé-García, M., Montoro-García, S. et al. New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells. Exp Mol Med 52, 281–292 (2020).

New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells

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Author: Alburquerque-González, Begoña1; Bernabé-García, Manuel2; Montoro-García, Silvia3;
Organizations: 1Pathology and Histology Department, Facultad de Ciencias de la Salud, UCAM Universidad Católica San Antonio de Murcia, Campus de los Jerónimos, s/n, 30107, Guadalupe, Murcia, Spain
2Research group “Telomerasa, Envejecimiento y Cáncer,” CIBERehd, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain
3Cell Culture Lab, Facultad de Ciencias de la Salud, UCAM Universidad Católica San Antonio de Murcia, Campus de los Jerónimos, s/n, Guadalupe, 30107, Murcia, Spain
4Research group “Regeneración, oncología molecular y TGF-β”, Institute for Biohealth Research from Murcia (IMIB), Hospital Clínico Universitario Virgen de la ArrixacaCarretera Madrid-Cartagena, El Palmar, Spain
5Cancer Research and Translational Medicine Research Unit, University of Oulu, Aapistie 5A, FI-90220, Oulu, Finland
6Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
7Department of Physical Chemistry and Institute of Biotechnology, University of Granada, Campus Fuentenueva s/n, 18071, Granada, Spain
8Institute of Oral and Maxillofacial Disease, University of Helsinki, Helsinki, Finland
9HUSLAB, Department of Pathology, Helsinki University Hospital, Helsinki, Finland
10Structural Bioinformatics and High Performance Computing (BIO-HPC) Research Group, Universidad Católica de Murcia (UCAM), Guadalupe, Spain
11Clinical Analysis Department, Group of Molecular Pathology and Pharmacogenetics, Institute for Biohealth Research from Murcia (IMIB), Hospital Universitario Santa Lucía, c/Mezquita sn, 30202, Cartagena, Spain
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5.3 MB)
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Language: English
Published: Springer Nature, 2020
Publish Date: 2020-05-11


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.

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Series: Experimental & molecular medicine
ISSN: 1226-3613
ISSN-E: 2092-6413
ISSN-L: 1226-3613
Volume: 52
Issue: 2
Pages: 281 - 292
DOI: 10.1038/s12276-020-0389-x
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This work is supported by the Instituto de Salud Carlos III (Spanish Ministry of Health) and FEDER funds (ref: PI15/00626). B.A.-G. belongs to the “Programa de Doctorado en ciencias de la Salud” from the Catholic University of Murcia (UCAM) and holds a predoctoral grant from UCAM. S.M.-G. was supported by the Fundación Séneca and PCR by the Finnish Cultural and Sigrid Juselius Foundations (2017–2018 and 2018–2019 grants).
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