2. Academic Validation
  3. Novel anti-invasive properties of a Fascin1 inhibitor on colorectal cancer cells

Novel anti-invasive properties of a Fascin1 inhibitor on colorectal cancer cells

  • J Mol Med (Berl). 2020 Mar;98(3):383-394. doi: 10.1007/s00109-020-01877-z.
Silvia Montoro-García 1,  Begoña Alburquerque-González 2,  Ángel Bernabé-García 3,  Manuel Bernabé-García 4,  Priscila Campioni Rodrigues 5 6,  Helena den-Haan 7,  Irene Luque 8,  Francisco José Nicolás 3,  Horacio Pérez-Sánchez 9,  María Luisa Cayuela 4,  Tuula Salo 5 6 10 11,  Pablo Conesa-Zamora 12 13
Affiliations

Affiliations

  • 1 Cell Culture Lab. Health Faculty, Universidad Católica de Murcia (UCAM), Campus de los Jerónimos, s/n, Guadalupe, 30107, Murcia, Spain. smontoro@ucam.edu.
  • 2 Pathology and Histology Department. Heatlh Faculty, Universidad Católica de Murcia (UCAM), Campus de los Jerónimos, s/n, Guadalupe, 30107, Murcia, Spain.
  • 3 Molecular Oncology and TGF-ß Lab, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Carretera Madrid-Cartagena. El Palmar, Murcia, Spain.
  • 4 Telomerase, Cancer and Aging Group, University Clinical Hospital "Virgen de la Arrixaca", Biomedical Research Institute of Murcia (IMIB-Arrixaca) Murcia, Murcia, Spain.
  • 5 Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, Aapistie 5A, FI-90220, Oulu, Finland.
  • 6 Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
  • 7 Eurofins Villapharma Research, Parque Tecnológico de Fuente Álamo. Ctra. El Estrecho-Lobosillo, Km 2,5. Av. Azul E, 30320, Murcia, Spain.
  • 8 Department of Physical Chemistry and Institute of Biotechnology, University of Granada, Campus Fuentenueva s/n 18071 Granada, Granada, Spain.
  • 9 Structural Bioinformatics and High Performance Computing (BIO-HPC) Research Group, Universidad Católica de Murcia (UCAM), Guadalupe, Spain.
  • 10 Institute of Oral and Maxillofacial Disease, University of Helsinki, Helsinki, Finland.
  • 11 HUSLAB, Department of Pathology, Helsinki University Hospital, Helsinki, Finland.
  • 12 Pathology and Histology Department. Heatlh Faculty, Universidad Católica de Murcia (UCAM), Campus de los Jerónimos, s/n, Guadalupe, 30107, Murcia, Spain. pablo.conesa@carm.es.
  • 13 Clinical Analysis Department, Group of Molecular Pathology and Pharmacogenetics, Biomedical Research Institute from Murcia (IMIB), Hospital Universitario Santa Lucía, c/Mezquita sn, 30202, Cartagena, Spain. pablo.conesa@carm.es.
PMID: 31996952 DOI: 10.1007/s00109-020-01877-z
Abstract

Tumor invasion and metastasis involve processes in which actin Cytoskeleton rearrangement induced by Fascin1 plays a crucial role. Indeed, Fascin1 has been found overexpressed in tumors with worse prognosis. Migrastatin and its analogues target Fascin1 and inhibit its activity. However, there is need for novel and smaller Fascin1 inhibitors. The aim of this study was to assess the effect of compound G2 in colorectal Cancer cell lines and compare it to migrastatin in in vitro and in vivo assays. Molecular modeling, actin-bundling, cell viability, inmunofluorescence, migration, and invasion assays were carried out in order to test anti-migratory and anti-invasive properties of compound G2. In addition, the in vivo effect of compound G2 was evaluated in a zebrafish model of invasion. HCT-116 cells exhibited the highest Fascin1 expression from eight tested colorectal Cancer cell lines. Compound G2 showed important inhibitory effects on actin bundling, filopodia formation, migration, and invasion in different cell lines. Moreover, compound G2 treatment resulted in significant reduction of invasion of DLD-1 overexpressing Fascin1 and HCT-116 in zebrafish larvae xenografts; this effect being less evident in Fascin1 known-down HCT-116 cells. This study proves, for the first time, the in vitro and in vivo anti-tumoral activity of compound G2 on colorectal Cancer cells and guides to design improved compound G2-based Fascin1 inhibitors. KEY MESSAGES: • Fascin is crucial for tumor invasion and metastasis and is overexpressed in bad prognostic tumors. • Several adverse tumors overexpress Fascin1 and lack targeted therapy. • Anti-fascin G2 is for the first time evaluated in colorectal carcinoma and compared with migrastatin. • Filopodia formation, migration activity, and invasion in vitro and in vivo assays were performed. • G2 blocks actin structures, migration, and invasion of colorectal Cancer cells as fascin-dependent.

Keywords

Colorectal cancer; Fascin1; Invasion; Migrastatin; Migration; Zebrafish xenograft.

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