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Activation of RhoB by Hypoxia Controls Hypoxia-Inducible Factor-1 Stabilization through Glycogen Synthase Kinase-3 in U87 Glioblastoma Cells

¹ Institut National de la Sante et de la Recherche Medicale U563, Departement d'Innovation Thérapeutique et Oncologie Moléculaire and ² Departement de Radiothérapie, Centre de Lutte Contre le Cancer Claudius Regaud, Toulouse Cedex, France

Requests for reprints: Elizabeth Cohen-Jonathan-Moyal, Departement de Radiothérapie, Centre de Lutte Contre le Cancer Claudius Regaud, 20-24 rue du Pont St. Pierre, 31052 Toulouse Cedex, France. Phone: 33-5-6142-4178; Fax: 33-5-6142-4643; E-mail: moyal{at}icr.fnclcc.fr or Christine Toulas, INSERM U563, Departement d'Innovation Thérapeutique et Oncologie Moléculaire, Departement de Radiothérapie, Centre de Lutte Contre le Cancer Claudius Regaud, 20-24 rue du Pont St Pierre, 31052 Toulouse Cedex, France. Phone: 33-5-6142-4275; Fax: 33-5-6142-4631; E-mail: toulas{at}icr.fnclcc.fr.

Hypoxia is a crucial factor in tumor aggressiveness and resistance to treatment, particularly in glioma. Our previous results have shown that inhibiting the small GTPase RhoB increased oxygenation of U87 human glioblastoma xenografts, in part, by regulating angiogenesis. We investigated here whether RhoB might also control a signaling pathway that would permit glioma cells to adapt to hypoxia. We first showed that silencing RhoB with siRNA induced degradation and inhibition of the transcriptional activity of the hypoxia-inducible factor by the proteasome in U87 hypoxic cells. This RhoB-dependent degradation of hypoxia-inducible factor-1 in hypoxic conditions was mediated by the Akt/glycogen synthase kinase-3ß pathway. While investigating how hypoxia could activate this signaling pathway, using the GST-Rhotekin RBD pulldown assay, we showed the early activation of RhoB by reactive oxygen species under hypoxic conditions and, subsequently, its participation in the ensuing cellular adaptation to hypoxia. Overall, therefore, our results have not only highlighted a new signaling pathway for hypoxia controlled by the small GTPase RhoB, but they also strongly implicate RhoB as a potentially important therapeutic target for decreasing tumor hypoxia. (Cancer Res 2006; 66(1): 482-9)

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