Nitrosoureas inhibit the stathmin-mediated migration and invasion of malignant glioma cells.
Nitrosoureas inhibit the stathmin-mediated migration and invasion of malignant glioma cells.
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DOI：
10.1158/0008-5472.can-07-6482
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发表时间：
2008-07-01
期刊：
影响因子：
11.2
通讯作者：
Park JK
中科院分区：
文献类型：
--
作者：
Liang XJ;Choi Y;Sackett DL;Park JK
恶性胶质瘤是最常见的脑内原发肿瘤，具有很高的致命性。肿瘤细胞从肿瘤形成的初始部位向周围脑组织的广泛迁移和侵袭使这些病变难以进行明确的手术治疗。Stathmin是一种微管不稳定蛋白，介导细胞周期进程，也可以调节定向细胞运动。亚硝脲，传统上被视为DNA烷化剂，也可以共价修饰蛋白质，如stathmin。因此，我们试图确定stathmin在恶性胶质瘤细胞运动、迁移和侵袭中的作用，并确定亚硝酸根对这些细胞运动相关过程的影响。采用划痕愈合恢复、Boyden小室迁移、Matrigel侵袭和器官型切片侵袭的方法，在细胞STATHMIN水平下调前后以及在亚致死性亚硝脲(CCNU；[1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]))浓度存在的情况下进行检测。我们证明，Stathmin表达的减少会显著降低恶性胶质瘤细胞的运动性、迁移性和侵袭性。在10μM的浓度下，即使在对细胞活力没有任何影响的情况下，也会引起类似的显著下降。CCNU对stathmin的直接抑制可能是一个促成因素。这些发现表明，抑制stathmin的表达和功能可能有助于限制恶性胶质瘤在脑内的扩散，亚硝脲除了具有抗增殖作用外，还可能具有治疗作用。
Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of nitrosoureas on these cell movement related processes. Scratch-wound healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down regulation of cellular stathmin levels and in the absence and presence of sub-lethal nitrosourea (CCNU; [1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]) concentrations. We demonstrate that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 μM, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain and that nitrosoureas may have therapeutic benefits in addition to their anti-proliferative effects.