Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2.
Primary brain tumors (gliomas) have the unusual ability to diffusely infiltrate the normal brain thereby evading surgical treatment. Chlorotoxin is a scorpion toxin that specifically binds to the surface of glioma cells and impairs their ability to invade. Using a recombinant His-Cltx we isolated and identified the principal Cltx receptor on the surface of glioma cells as matrix metalloproteinase-2 (MMP-2). MMP-2 is specifically up-regulated in gliomas and related cancers, but is not normally expressed in brain. We demonstrate that Cltx specifically and selectively interacts with MMP-2 isoforms, but not with MMP-1, -3, and -9, which are also expressed in malignant glioma cells. Importantly, we show that the anti-invasive effect of Cltx on glioma cells can be explained by its interactions with MMP-2. Cltx exerts a dual effect on MMP-2: it inhibits the enzymatic activity of MMP-2 and causes a reduction in the surface expression of MMP-2. These findings suggest that Cltx is a specific MMP-2 inhibitor with significant therapeutic potential for gliomas and other diseases that invoke the activity of MMP-2.
Deshane
Jessy
J
Department of Neurobiology and Civitan International Research Center, University of Alabama, Birmingham 35294, USA.
Garner
Craig C
CC
Sontheimer
Harald
H
D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D002384:Catalysis; D002462:Cell Membrane / Q000201:enzymology; D005910:Glioma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D012604:Scorpion Venoms / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D012604:Scorpion Venoms; C091539:Chlorotoxin; D020778:Matrix Metalloproteinase 2