Abstract 2330: MMP-2 regulates Rac1- and Cdc42-mediated cell migration via integrin αVβ3/FAK in U87 and U251 glioblastoma cell lines

Abstract

Abstract Gliomas, the most common form of brain tumors, are characterized by a capacity to invade through normal brain tissue. This infiltrative character is the hallmark of poor prognosis. A greater understanding of the molecular determinants that drive cell motility may lead to improved therapy. The molecules of the extracellular matrix are involved in organization of the cytoskeleton and activation of intracellular signaling that is required for the regulation of cell adhesion and migration. Here, we show that the downregulation of matrix metalloproteinase-2 (MMP-2; gelatinase A) using an adenoviral vector expressing siRNA (Ad-MMP-2-Si) inhibited cell migration in U87 and U251 glioblastoma cell lines as determined by spheroid migration and wound-healing assays. Transcriptional inactivation of MMP-2 altered interaction of MMP-2 and the integrin-αVβ3 as determined by immunoprecipitation and co-localization studies. In addition, downregulation of MMP-2 inhibited the complex formation of FAK, integrin-αVβ3 and 14-3-3ζ, which in turn decreased the activation of GTP-bound forms of Rac1 and Cdc42. Transfection of the cells with constitutively active Rac1 and Cdc42 reversed Ad-MMP-2-Si-blocked cell migration and gelatin degrading. Further, administration of recombinant human MMP-2 reversed MMP-2 siRNA-inhibited GTP-bound forms of Rac1 and Cdc42. Additionally, functionally blocking integrin-αVβ3 antibody inhibited GTP-bound forms of Rac1 and Cdc42, thereby revealing that the interaction of MMP-2 and integrin-αVβ3 plays a critical role in cell migration. In summary, our data demonstrate that the inhibition of MMP-2 inhibits integrin-αVβ3/FAK-mediated migration by reducing the GTP-bound forms of Rac1 and Cdc42 in U87 and U251 glioblastoma cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2330.