A small-molecule RGD-integrin antagonist inhibits cell adhesion, cell migration and induces anoikis in glioblastoma cells

Russo,Marika  A.; Paolillo,Mayra; Sanchez-Hernandez,Yuly; Curti,Daniela; Ciusani,Emilio; Serra,Massimo; Colombo,Lino; Schinelli,Sergio

doi:10.3892/ijo.2012.1708

A small-molecule RGD-integrin antagonist inhibits cell adhesion, cell migration and induces anoikis in glioblastoma cells

Authors:
- Marika A. Russo
- Mayra Paolillo
- Yuly Sanchez-Hernandez
- Daniela Curti
- Emilio Ciusani
- Massimo Serra
- Lino Colombo
- Sergio Schinelli
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Affiliations: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA, Department of Drug Sciences, University of Pavia, I-27100 Pavia, Italy, Department of Biology and Biotechnology ‘Lazzaro Spallanzani’, University of Pavia, I-27100 Pavia, Italy, Carlo Besta Neurological Institute, I-20133 Milan, Italy
Published online on: November 20, 2012 https://doi.org/10.3892/ijo.2012.1708
Pages: 83-92
Copyright: © Russo et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

In cancer cells integrins modulate important cellular events that regulate the metastasic cascade which involves detachment from the tumor mass, dissemination and attachment to the oncogenic niche. The α5β1, αvβ3 and αvβ5 integrins are widely expressed in different cancer types and recognize the tripeptide Arg-Gly-Asp (RGD) motif present in several extracellular matrix proteins. In human glioblastoma, αvβ3 integrin expression correlates with tumor grade, suggesting that this integrin may play a crucial role in the highly infiltrative behavior of high grade gliomas. However, few selective RGD-like antagonists have been developed and few studies have investigated their effects in in vitro models of human glioblastoma. In this study, we investigated several cellular effects and the underlying molecular mechanisms exerted by a new small-molecule RGD antagonist, 1a-RGD, in the U251 and U373 human glioblastoma cell lines. Treatment with 1a-RGD (20 µM) demonstrated a weak effect on cell viability and cell proliferation but strongly inhibited cell attachment and cell migration together with actin cytoskeleton disassembly. Prolonged 1a-RGD treatment (72 h) induced anoikis, assessed by Annexin staining and nucleosome assay, particularly in the detached cells. When integrin-linked transduction pathways were investigated, 1aRGD was found to exert a marked reduction in focal adhesion kinase (FAK) phosphorylation without affecting the AKT- and ERK-dependent pathways. Our data indicate that 1a-RGD, probably via modulation of the FAK-dependent pathway, inhibits cell migration and attachment and induces anoikis in glioblastoma cells. This novel finding suggests that the development of an RGD-like molecule may represent a promising tool for the pharmacological approach aimed at reducing the malignancy of glioblastoma cells.

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