The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells 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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/4/861 |
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| author | Begoña Alburquerque-González Ángel Bernabé-García Manuel Bernabé-García Javier Ruiz-Sanz Fernando Feliciano López-Calderón Leonardo Gonnelli Lucia Banci Jorge Peña-García Irene Luque Francisco José Nicolás María Luisa Cayuela-Fuentes Enrico Luchinat Horacio Pérez-Sánchez Silvia Montoro-García Pablo Conesa-Zamora |
| author_facet | Begoña Alburquerque-González Ángel Bernabé-García Manuel Bernabé-García Javier Ruiz-Sanz Fernando Feliciano López-Calderón Leonardo Gonnelli Lucia Banci Jorge Peña-García Irene Luque Francisco José Nicolás María Luisa Cayuela-Fuentes Enrico Luchinat Horacio Pérez-Sánchez Silvia Montoro-García Pablo Conesa-Zamora |
| author_sort | Begoña Alburquerque-González |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T00:45:22Z |
| format | Article |
| id | doaj.art-1a1c66556b4743058dd3f6aa40dbbe5f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T00:45:22Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-1a1c66556b4743058dd3f6aa40dbbe5f2023-12-11T17:30:34ZengMDPI AGCancers2072-66942021-02-0113486110.3390/cancers13040861The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In VivoBegoña Alburquerque-González0Ángel Bernabé-García1Manuel Bernabé-García2Javier Ruiz-Sanz3Fernando Feliciano López-Calderón4Leonardo Gonnelli5Lucia Banci6Jorge Peña-García7Irene Luque8Francisco José Nicolás9María Luisa Cayuela-Fuentes10Enrico Luchinat11Horacio Pérez-Sánchez12Silvia Montoro-García13Pablo Conesa-Zamora14Department of Pathology and Histology, Campus de los Jerónimos, UCAM Universidad Católica San Antonio de Murcia, s/n, 30107 Murcia, SpainLaboratorio de Regeneración, Oncología Molecular y TGF-ß, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Carretera Madrid-Cartagena, El Palmar, 30120 Murcia, SpainTelomerase, Cancer and Aging Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, SpainDepartment 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, SpainDepartment of Pathology and Histology, Campus de los Jerónimos, UCAM Universidad Católica San Antonio de Murcia, s/n, 30107 Murcia, SpainCERM—Magnetic Resonance Center, Università degli Studi di Firenze, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, ItalyCERM—Magnetic Resonance Center, Università degli Studi di Firenze, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, ItalyStructural 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, SpainDepartment 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, SpainLaboratorio de Regeneración, Oncología Molecular y TGF-ß, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Carretera Madrid-Cartagena, El Palmar, 30120 Murcia, SpainTelomerase, Cancer and Aging Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, SpainCERM—Magnetic Resonance Center, Università degli Studi di Firenze, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, ItalyStructural 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, SpainCell Culture Lab, Facultad de Ciencias de la Salud, Campus de los Jerónimos, s/n, UCAM Universidad Católica San Antonio de Murcia, Guadalupe, 30107 Murcia, SpainLaboratory Medicine Department, Group of Molecular Pathology and Pharmacogenetics, Biomedical Research Institute from Murcia (IMIB), Hospital Universitario Santa Lucía, c/Mezquita sn, 30202 Cartagena, SpainBackground: 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.https://www.mdpi.com/2072-6694/13/4/861Fascin1raltegravirmigrastatininvasionmigrationzebrafish xenograft |
| spellingShingle | Begoña Alburquerque-González Ángel Bernabé-García Manuel Bernabé-García Javier Ruiz-Sanz Fernando Feliciano López-Calderón Leonardo Gonnelli Lucia Banci Jorge Peña-García Irene Luque Francisco José Nicolás María Luisa Cayuela-Fuentes Enrico Luchinat Horacio Pérez-Sánchez Silvia Montoro-García Pablo Conesa-Zamora The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo Cancers Fascin1 raltegravir migrastatin invasion migration zebrafish xenograft |
| title | The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo |
| title_full | The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo |
| title_fullStr | The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo |
| title_full_unstemmed | The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo |
| title_short | The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo |
| title_sort | fda approved antiviral raltegravir inhibits fascin1 dependent invasion of colorectal tumor cells in vitro and in vivo |
| topic | Fascin1 raltegravir migrastatin invasion migration zebrafish xenograft |
| url | https://www.mdpi.com/2072-6694/13/4/861 |
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