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_vβ₃/_vβ₅ Integrins-FAK-RhoB: A Novel Pathway for Hypoxia Regulation in Glioblastoma

¹ Institut National de la Santé et de la Recherche Médicale (INSERM) U563, Department of Signaling, Oncogenesis, and Therapeutic Innovation, and ² Department of Radiation, Institut Claudius Regaud, Toulouse, France

Requests for reprints: Elizabeth Cohen-Jonathan Moyal, INSERM U563, Institut Claudius Regaud, 20-24 rue du Pont St-Pierre, 31052 Toulouse, France. Phone: 33-5-61-42-41-78; Fax: 33-5-61-42-46-43; E-mail: moyal.elizabeth{at}claudiusregaud.fr, or Christine Toulas, Institut Claudius Regaud, INSERM U563, 20-24 rue du Pont St-Pierre, 31052 Toulouse, France. Phone: 33-5-61-42-42-75; Fax: 33-5-61-42-46-31; E-mail: toulas.christine{at}claudiusregaud.fr.

Key Words: FAK/RhoB • hypoxia • integrin

The presence of hypoxic areas in glioblastoma is an important determinant in tumor response to therapy and, in particular, to radiotherapy. Here we have explored the involvement of integrins, up to now known as regulators of angiogenesis and invasion, in the regulation of tumor hypoxia driven from the tumor cell. We first show that hypoxia induces the recruitment of _vβ₃ and _vβ₅ integrins to the cellular membrane of U87 and SF763 glioblastoma cells, thereby activating the focal adhesion kinase (FAK). We then show that inhibiting _vβ₃ or _vβ₅ integrins in hypoxic cells with a specific inhibitor or with siRNA decreases the hypoxia-inducible factor 1 (HIF-1) intracellular level. This integrin-dependent regulation of HIF-1 is mediated through the regulation of FAK, which in turn activates the small GTPase RhoB, leading to the inhibition of GSK3-β. Furthermore, silencing this pathway in glioma cells of established xenografts dramatically reduces glioma hypoxia, associated with a significant decrease in vessel density. Our present results unravel a new mechanism of hypoxia regulation by establishing the existence of an _vβ₃/_vβ₅ integrin–dependent loop of hypoxia autoregulation in glioma. Targeting this hypoxia loop may be crucial to optimizing radiotherapy efficiency. [Cancer Res 2009;69(8):3308–16]