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Inhibition of Rho pathways induces radiosensitization and oxygenation in human glioblastoma xenografts

Oncogene volume 22, pages 8861–8869 (2003)Cite this article

Abstract

We previously demonstrated in vitro that inhibiting the biological pathways of the small GTPase Rho radiosensitizes the human glioma U87 cell line. The aim of this study was to determine if Rho might be involved in the control of in vivo radiosensitivity altogether by controlling cellular radioresistance and by modifying tumor microenvironment. We demonstrate here that the in vivo induction of the dominant negative of Rho, RhoBN19, in U87 xenografts induces a significant decrease of tumor cell survival after irradiation more important than the one we previously observed in vitro. This in vivo increased effect of RhoBN19 expression is due to the improvement of the tumor oxygenation associated with a significant decrease of the vessel density and of the metalloproteinase 2 (MMP2) expression. Moreover, in vitro RhoBN19 expression in U87 cells leads to the inhibition of MMP2 activity. Our results demonstrate for the first time that inhibiting Rho pathways modifies the in vivo radiosensitivity of human glioma cells by controlling intrinsic radioresistance, hypoxia and angiogenesis. These data strongly suggest that Rho should be a major determinant of cellular resistance to ionizing radiation.

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Acknowledgements

We thank Dr Cameron Koch, University of Pennsylvania, for providing EF5 and Cy3-conjugated ELK-51 and Dr John White for providing us with pGRE5.2 plasmid. This work has been supported by the Ministere de la Recherche et de l’Enseignement Supérieur (IA, GF, ECJ), by the Groupe de Recherche de l’Institut Claudius Regaud (CT, ECJ) and by Electricité de France.

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Authors and Affiliations

  1. Département Innovation Thérapeutique et Oncologie Moléculaire INSERM U563, Institut Claudius Regaud, 20-24 rue du Pont St Pierre, Toulouse Cedex, 31052, France

    Isabelle Ader, Caroline Delmas, Gilles Favre, Christine Toulas & Elizabeth Cohen-Jonathan-Moyal

  2. Département de Radiothérapie, Institut Claudius Regaud, 20-24 rue du Pont St Pierre, Toulouse Cedex, 31052, France

    Jacques Bonnet & Elizabeth Cohen-Jonathan-Moyal

  3. Laboratoire d’anatomic-pathologique, Institut Claudius Regaud, 20-24 rue du Pont St Pierre, Toulouse Cedex, 31052, France

    Philippe Rochaix

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  1. Isabelle Ader
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Correspondence to Elizabeth Cohen-Jonathan-Moyal.

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Ader, I., Delmas, C., Bonnet, J. et al. Inhibition of Rho pathways induces radiosensitization and oxygenation in human glioblastoma xenografts. Oncogene 22, 8861–8869 (2003). https://doi.org/10.1038/sj.onc.1207095

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