17-Allylamino-17-Demethoxygeldanamycin Down-Regulates Hyaluronic Acid-Induced Glioma Invasion by Blocking Matrix Metalloproteinase-9 Secretion

Abstract

Hyaluronic acid (HA) has been implicated in cell adhesion, motility, and tumor progression in gliomas. We previously reported that HA stimulates secretion of matrix metalloproteinase-9 (MMP-9) and induces glioma invasion. However, the molecular mechanism of HA action and therapeutic strategies for blocking HA-induced MMP-9 secretion remain unknown. Here, we report that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) blocks MMP-9 secretion and that HA-induced nuclear factor-kappa B (NF-kappa B) activation is mediated by I kappa B kinase, which phosphorylates the NF-kappa B inhibitor I kappa B alpha and promotes its degradation. In addition, using an RNA interference approach, we show that the focal adhesion kinase plays a critical role in mediating HA-induced NF-kappa B activation; which resulted in increased MMP-9 expression and secretion, cell migration, and invasion. Importantly, we show that 17-AAG acts by blocking focal adhesion kinase activation, thereby inhibiting I kappa B kinase-dependent I kappa B alpha,, phosphorylation/degradation, NF-kappa B activation, and MMP-9 expression. This leads to suppression of HA-induced cell migration and invasion. Based on our data, we propose that 17-AAG is a candidate drug for treatment of highly invasive gliomas resulting from HA-induced, NF-kappa B-mediated MMP-9 secretion. (Mol Cancer Res 2008;6(11):1657-65)