Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2
Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2
复制标题
DOI：
10.1074/jbc.m205662200
复制
发表时间：
2003-02-07
影响因子：
4.8
通讯作者：
Sontheimer, H
中科院分区：
文献类型：
--
作者：
Deshane, J;Garner, CC;Sontheimer, H
原发性脑肿瘤（神经胶质瘤）具有不寻常的扩散性浸润正常脑的能力，从而逃避手术治疗。Chlorotoxin是一种蝎毒素，它能特异性地与神经胶质瘤细胞表面结合，并削弱它们的侵袭能力。使用重组His-Cltx，我们分离并鉴定了胶质瘤细胞表面的主要Cltx受体为基质金属蛋白酶-2（MMP-2）。MMP-2在神经胶质瘤和相关癌症中特异性上调，但在脑中不正常表达。我们证明，Cltx特异性和选择性地与MMP-2亚型相互作用，但不与MMP-1，-3，和-9，这也是在恶性胶质瘤细胞中表达。重要的是，我们发现Cltx对胶质瘤细胞的抗侵袭作用可以通过其与MMP-2的相互作用来解释。Cltx对MMP-2发挥双重作用：它抑制MMP-2的酶活性并导致MMP-2的表面表达减少。这些发现表明，Cltx是一种特异性MMP-2抑制剂，对神经胶质瘤和其他引起MMP-2活性的疾病具有显著的治疗潜力。
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 upregulated 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.