Ect2 Regulates Fn14-Rac1 Induced Glioma Invasion
Ennis, Matthew J.1,2; Tran, Nhan L.2; Armstrong, Brock A.2; Fortin, Shannon P.1,2; McDonough, Wendy S.2; and Berens, Michael E.2
1Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ; 2Cancer and Cell Biology Division; Translational Genomics Research Institute, Phoenix, AZ
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, biologically unique by virtue of the proclivity for local invasion into the adjacent normal brain tissue and the rarity of systemic metastasis. We previously reported that the transmembrane receptor, fibroblast growth factor-inducible 14 (Fn14), expression level is elevated in advanced glial tumors and also up-regulated in migrating glioma cells in vitro and invading cells in vivo. Fn14 serves as a cell surface receptor for the multifunctional cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK). We have found that Fn14-induced glioma invasion is mediated by the small GTPase Rac1; Rac1 is a ubiquitous signaling protein operating in many normal tissues, consequently therapeutic targeting of Rac1 would likely have complex and toxic effects on normal cells; however the central position of Rac1 as a downstream player in many signaling pathologies operating in malignant states, suggest that targeting key regulators of Rac1 will be more effective as a therapy toward invading glioma cells. In this study, we found that Ect2, a guanine nucleotide exchange factor (GEF), is overexpressed in GBM, and that overexpression of Ect2 correlates directly with tumor grade and inversely with patient outcome. Our preliminary data show that Ect2 can associate with the Fn14 cytoplasmic complex and regulate Rac1 activation. Depletion of Ect2 by siRNA oligonucleotide abrogates TWEAK induced glioma migration. Thus, therapy designed to interfere with the function of Ect2 is likely to specifically target invasive glioblastoma cells.