17-Allylamino-17-demethoxygeldanamycin down-regulates hyaluronic acid-induced glioma invasion by blocking matrix metalloproteinase-9 secretion.
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-kappaB (NF-kappaB) activation is mediated by IkappaB kinase, which phosphorylates the NF-kappaB inhibitor IkappaBalpha 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-kappaB 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 IkappaB kinase-dependent IkappaBalpha phosphorylation/degradation, NF-kappaB 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-kappaB-mediated MMP-9 secretion.
Kim
Mi-Suk
MS
Research Institute and Hospital, National Cancer Center, Gyeonggi, Korea.
Kwak
Hee-Jin
HJ
Lee
Ji-Woo
JW
Kim
Hea-Jin
HJ
Park
Myung-Jin
MJ
Park
Jong-Bae
JB
Choi
Kyung-Ho
KH
Yoo
Heon
H
Shin
Sang-Hoon
SH
Shin
Woon-Seob
WS
Song
Eun-Sook
ES
Lee
Seung-Hoon
SH
D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000473:pathology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism* / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D020672:I-kappa B Proteins; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; C112765:tanespimycin; D006820:Hyaluronic Acid; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051550:I-kappa B Kinase; D020780:Matrix Metalloproteinase 9