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-KB (NF-KB) activation is mediated by IKB kinase, which phosphorylates the NF-KB inhibitor IKBA 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-KB 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 IKB kinasedependent IKBA phosphorylation/degradation, NF-KB 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-KB -mediated MMP-9

Fucosyltransferase IV Enhances Expression of MMP-12 Stimulated by EGF via the ERK1/2, p38 and NF-kB Pathways in A431Cells

“…NF-kB activity is regulated by the endogenous inhibitor, IkBα, and interaction with IkBα blocks the nuclear localization of NF-kB, keeping NF-kB it sequestered in the cytoplasm. In the current study we showed that EGF induced phosphorylation of IkB, which led to degradation of IkBα and to NF-kB nuclear translocation and transcriptional activation in A431 cells (Kim et al, 2008).…”

Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas

“…miR-21 facilitates glioma invasion through Ras/MAPK signaling Previously, we demonstrated that ERK1/2 and NF-kB signalings have important roles in HA-induced invasion of glioma cells lacking functional PTEN (Park et al, 2002;Kim et al, 2005Kim et al, , 2008. To examine the role of miR-21 in these pathways, we performed immunoblot analyses using relevant antibodies.…”

“…Glioma invasion assays were performed using modified Boyden chambers with polycarbonate nucleopore membranes (Corning, Corning, NY, USA), as described previously (Park et al, 2002;Kim et al, 2005Kim et al, , 2008. Invasiveness was determined by counting cells in five microscopic fields per well, and the extent of invasion was expressed as the average number of cells per microscopic field.…”

“…Cells were transfected with anti-control or antimiR21, incubated for 36 h and stimulated with 200 mg/ml HA for 18 h. The volume of conditioned media was normalized according to the cell number. The enzymatic activity of electrophoretically separated gelatinolytic enzymes in the conditioned media of glioma cells was determined by gelatin zymography, as described previously (Park et al, 2002;Kim et al, 2005Kim et al, , 2008. Zones of gelatinolytic activity were detected as clear bands against a blue background.…”

“…In spite of recent advances in our understanding of the proximal signal transduction pathways activated by HA, the molecular mechanism of HA-associated motility and invasion is not well understood. Previously, we reported that HA-induced metalloproteinase-9 (MMP-9) secretion and invasion of glioma cells lacking functional PTEN are mediated by ERK1/2 and NF-kB signaling (Park et al, 2002;Kim et al, 2005Kim et al, , 2008. However, it remains unclear how these signalings are amplified in a tumor-specific manner.…”