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

• Published in: Molecular cancer research Vol. 6; no. 11; pp. 1657 - 1665
• Main Authors: Kim, Mi-Suk, Kwak, Hee-Jin, Lee, Ji-Woo, Kim, Hea-Jin, Park, Myung-Jin, Park, Jong-Bae, Choi, Kyung-Ho, Yoo, Heon, Shin, Sang-Hoon, Shin, Woon-Seob, Song, Eun-Sook, Lee, Seung-Hoon
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.11.2008
• Subjects: 17-AAG; Benzoquinones - pharmacology; Cell Line, Tumor; Cell Movement; Cell Nucleus - metabolism; Down-Regulation; Enzyme Activation - drug effects; Extracellular Matrix - pathology; FAK; Focal Adhesion Protein-Tyrosine Kinases - metabolism; glioma; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - pharmacology; Humans; hyaluronic acid; Hyaluronic Acid - metabolism; Hyaluronic Acid - pharmacology; I-kappa B Kinase - metabolism; I-kappa B Proteins - metabolism; invasion; Lactams, Macrocyclic - pharmacology; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase 9 - secretion; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; NF-κB; Phosphorylation; RNA Interference; Signal Transduction
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-08-0034

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-κB (NF-κB) activation is mediated by IκB kinase, which phosphorylates the NF-κB inhibitor IκBα 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-κB 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 IκB kinase–dependent IκBα phosphorylation/degradation, NF-κB 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-κB–mediated MMP-9 secretion. (Mol Cancer Res 2008;6(11):1657–65)