Abstract 5140: Rsu1 and the IPP adhesion complex can regulate adhesion and migration in glioma cell lines

Abstract

Abstract One hallmark of high grade glioblastoma is invasive growth that is dependent on ability of the tumor cells to migrate from the tumor into surrounding brain tissue thus preventing complete surgical resection. Rsu1, a member of the Integrin Linked Kinase-PINCH1-Parvin (IPP) cell adhesion complex, is encoded by a gene on human chromosome 10p13 in a region frequently deleted in high grade gliomas. Previous studies from our lab demonstrated that ectopic expression of Rsu1 in a human glioma cell line inhibited the tumorigenicity of the cells. The current study addresses the effect of Rsu1 on adhesion and migration in human glioma cell lines. The results with stable Rsu1 transfectants in the U87 glioma cell line indicate that Rsu1 expression results in enlarged cells with increased filapodial extensions and an increase in the number of focal adhesions. This phenotype correlates with increased cell adhesion and 30-50% decreased cell migration in Boyden chamber assays using PDGF, TPA or HGF as inducers of migration. siRNA-mediated depletion of Rsu1 concomitantly reduces the level of other IPP proteins, particularly the Rsu1 binding protein PINCH1. This loss of cell adhesion proteins reduces adhesion and enhances in vitro migration of highly oncogenic tumor cells. Infection of U87 and U251 glioma cell lines or immortalized human astrocytes and their Ras-transformed counterparts with adenovirus encoding Rsu1 decreased or eliminated phosphorylation of Akt on serine 473 compared to control vector. This finding and previous work demonstrating that signaling through the JNK pathway can be influenced by Rsu1 and PINCH11,2,3 suggest that both JNK and PI-3-kinase pathways are regulated by Rsu1 to limit cell migration. These studies identify deletion of Rsu1 as a mechanism that inhibits the IPP complex -induced adhesion as a potential mediator of the migratory behavior of high grade gliomas exhibiting chromosome 10 loss or 10p13 deletion. 1. Masuelli, L and Cutler, ML, 1995. Mol. Cell Biol.16:5466-76. 2. Dougherty et al., 2008. Eur J. Cell Biol.87:721-34. 3. Kadrmas J et al., 2004. J. Cell Biol.167:1019-24. 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 5140.