The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFκB pathway activation and BCL-X_L/BCL-W expression

The Fn14 gene encodes a type Ia transmembrane protein that belongs to the tumor necrosis factor receptor superfamily. We recently showed that fibroblast growth factor-inducible 14 (Fn14) is overexpressed in migrating glioma cells in vitro and in glioblastoma multiforme clinical specimens in vivo. To determine the biological role of Fn14 in brain cancer progression, we examined the activity of Fn14 as a potential mediator of cell survival. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-stimulated glioma cells had increased cellular resistance to cytotoxic therapy-induced apoptosis. Either TWEAK treatment or Fn14 overexpression in glioma cells resulted in the activation of NFκB and subsequently the translocation of NFκB from the cytoplasm to the nucleus. In addition, Fn14 activation induced BCL-X _L and BCL-W mRNA and protein levels, and this effect was dependent upon NFκB transcriptional activity. Substitution of a putative NFκB binding site identified in the BCL-X promoter significantly decreased Fn14-induced transactivation. Furthermore Fn14-induced transactivation of the BCL-X promoter was also diminished by the super-repressor IκBα mutant, which specifically inhibits NFκB activity, and by mutations in the NFκB binding motif of the BCL-X promoter. Additionally small interfering RNA-mediated depletion of either BCL-X_L or BCL-W antagonized the TWEAK protective effect on glioma cells. Our results suggest that NFκB-mediated up-regulation of BCL-X_L and BCL-W expression in glioma cells increases cellular resistance to cytotoxic therapy-induced apoptosis. We propose that the Fn14 protein functions, in part, through the NFκB signaling pathway to up-regulate BCL-X_L and BCL-W expression to foster malignant glioblastoma cell survival. Targeted therapy against Fn14 as an adjuvant to surgery may improve management of invasive glioma cells and advance the outcome of this devastating cancer.