17-Allylamino-17-Demethoxygeldanamycin Down-Regulates Hyaluronic Acid-Induced Glioma Invasion by Blocking Matrix Metalloproteinase-9 Secretion
- 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
- Issue Date
- Nov-2008
- Publisher
- AMER ASSOC CANCER RESEARCH
- Citation
- MOLECULAR CANCER RESEARCH, v.6, no.11, pp 1657 - 1665
- Pages
- 9
- Journal Title
- MOLECULAR CANCER RESEARCH
- Volume
- 6
- Number
- 11
- Start Page
- 1657
- End Page
- 1665
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/14157
- DOI
- 10.1158/1541-7786.MCR-08-0034
- ISSN
- 1541-7786
1557-3125
- 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)
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