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Nitrosoureas Inhibit the Stathmin-Mediated Migration and Invasion of Malignant Glioma Cells

¹ Surgical and Molecular Neuro-oncology Unit, National Institute of Neurological Disorders and Stroke and ² Laboratory of Integrative and Medical Biophysics, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland; and ³ National Center of Nanoscience and Technology of China, Zhongguancun, Beijing, China

Requests for reprints: John K. Park, 35 Convent Drive, Bethesda, MD 20892-3706. Phone: 301-402-6935; Fax: 1-301-480-0099; E-mail: parkjk{at}ninds.nih.gov.

Key Words: stathmin • malignant gliomas • nitrosoureas • migration • invasion • glioblastoma

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 sublethal nitrosourea ([1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]; CCNU) concentrations. We show that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 µmol/L, 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 antiproliferative effects. [Cancer Res 2008;68(13):5267–72]