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Article

The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo

1
Department of Pathology and Histology, Campus de los Jerónimos, UCAM Universidad Católica San Antonio de Murcia, s/n, 30107 Murcia, Spain
2
Laboratorio de Regeneración, Oncología Molecular y TGF-ß, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Carretera Madrid-Cartagena, El Palmar, 30120 Murcia, Spain
3
Telomerase, Cancer and Aging Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, Spain
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Department of Physical Chemistry, Institute of Biotechnology and Excellence Research Unit of “Chemistry Applied to Biomedicine and the Environment, Spain Campus Fuentenueva s/n, University of Granada, 18071 Granada, Spain
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CERM—Magnetic Resonance Center, Università degli Studi di Firenze, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy
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Dipartimento di Chimica, Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy
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Structural Bioinformatics and High Performance Computing (BIO-HPC) Research Group, Campus de los Jerónimos, s/n, UCAM Universidad Católica San Antonio de Murcia, Guadalupe, 30107 Murcia, Spain
8
Consorzio per lo Sviluppo dei Sistemi a Grande Interfase—CSGI, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy
9
Cell Culture Lab, Facultad de Ciencias de la Salud, Campus de los Jerónimos, s/n, UCAM Universidad Católica San Antonio de Murcia, Guadalupe, 30107 Murcia, Spain
10
Laboratory Medicine Department, Group of Molecular Pathology and Pharmacogenetics, Biomedical Research Institute from Murcia (IMIB), Hospital Universitario Santa Lucía, c/Mezquita sn, 30202 Cartagena, Spain
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Academic Editor: Serge Roche
Cancers 2021, 13(4), 861; https://doi.org/10.3390/cancers13040861
Received: 28 January 2021 / Revised: 12 February 2021 / Accepted: 15 February 2021 / Published: 18 February 2021
(This article belongs to the Special Issue Fascin in Cancer, from Prognostic Marker to Molecular Target)
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. Serrated adenocarcinoma (SAC) has been recently recognized by the WHO as a histological CRC with bad prognosis. Consistent with previous evidence, our group identified Fascin1 as a protein directly related to the invasiveness of tumor cells, overexpressed and positively correlated with worse survival in various carcinomas, including SAC. Therefore, Fascin1 has emerged as an ideal target for cancer treatment. In the present study, virtual screening has been carried out from a library of 9591 compounds, thus identifying the FDA-approved anti-retroviral raltegravir (RAL) as a potential Fascin1 blocker. In vitro and in vivo results show that RAL exhibits Fascin1-binding activity and Fascin1-dependent anti-invasive and anti-metastatic properties against CRC cells both in vitro and in vivo.
Background: Fascin1 is the key actin-bundling protein involved in cancer invasion and metastasis whose expression is associated with bad prognosis in tumor from different origins. Methods: In the present study, virtual screening (VS) was performed for the search of Fascin1 inhibitors and RAL, an FDA-approved inhibitor of human immunodeficiency virus-1 (HIV-1) integrase, was identified as a potential Fascin1 inhibitor. Biophysical techniques including nuclear magnetic resonance (NMR) and differential scanning fluorimetry (DSF) were carried out in order to confirm RAL as a Fascin1 blocker. The effect of RAL on actin-bundling activity Fascin1 was assessed by transmission electron microscopy (TEM), immunofluorescence, migration, and invasion assays on two human colorectal adenocarcinoma cell lines: HCT-116 and DLD-1. In addition, the anti-metastatic potential of RAL was in vivo evaluated by using the zebrafish animal model. Results: NMR and DSF confirmed in silico predictions and TEM demonstrated the RAL-induced disorganization of the actin structure compared to control conditions. The protrusion of lamellipodia in cancer cell line overexpressing Fascin1 (HCT-116) was abolished in the presence of this drug. By following the addition of RAL, migration of HCT-116 and DLD-1 cell lines was significantly inhibited. Finally, using endogenous and exogenous models of Fascin1 expression, the invasive capacity of colorectal tumor cells was notably impaired in the presence of RAL in vivo assays; without undesirable cytotoxic effects. Conclusion: The current data show the in vitro and in vivo efficacy of the antiretroviral drug RAL in inhibiting human colorectal cancer cells invasion and metastasis in a Fascin1-dependent manner. View Full-Text
Keywords: Fascin1; raltegravir; migrastatin; invasion; migration; zebrafish xenograft; colorectal cancer Fascin1; raltegravir; migrastatin; invasion; migration; zebrafish xenograft; colorectal cancer
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MDPI and ACS Style

Alburquerque-González, B.; Bernabé-García, Á.; Bernabé-García, M.; Ruiz-Sanz, J.; López-Calderón, F.F.; Gonnelli, L.; Banci, L.; Peña-García, J.; Luque, I.; Nicolás, F.J.; Cayuela-Fuentes, M.L.; Luchinat, E.; Pérez-Sánchez, H.; Montoro-García, S.; Conesa-Zamora, P. The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo. Cancers 2021, 13, 861. https://doi.org/10.3390/cancers13040861

AMA Style

Alburquerque-González B, Bernabé-García Á, Bernabé-García M, Ruiz-Sanz J, López-Calderón FF, Gonnelli L, Banci L, Peña-García J, Luque I, Nicolás FJ, Cayuela-Fuentes ML, Luchinat E, Pérez-Sánchez H, Montoro-García S, Conesa-Zamora P. The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo. Cancers. 2021; 13(4):861. https://doi.org/10.3390/cancers13040861

Chicago/Turabian Style

Alburquerque-González, Begoña, Ángel Bernabé-García, Manuel Bernabé-García, Javier Ruiz-Sanz, Fernando F. López-Calderón, Leonardo Gonnelli, Lucia Banci, Jorge Peña-García, Irene Luque, Francisco J. Nicolás, María L. Cayuela-Fuentes, Enrico Luchinat, Horacio Pérez-Sánchez, Silvia Montoro-García, and Pablo Conesa-Zamora. 2021. "The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo" Cancers 13, no. 4: 861. https://doi.org/10.3390/cancers13040861

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