The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/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 NFkappaB and subsequently the translocation of NFkappaB from the cytoplasm to the nucleus. In addition, Fn14 activation induced BCL-XL and BCL-W mRNA and protein levels, and this effect was dependent upon NFkappaB transcriptional activity. Substitution of a putative NFkappaB 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 IkappaBalpha mutant, which specifically inhibits NFkappaB activity, and by mutations in the NFkappaB binding motif of the BCL-X promoter. Additionally small interfering RNA-mediated depletion of either BCL-XL or BCL-W antagonized the TWEAK protective effect on glioma cells. Our results suggest that NFkappaB-mediated up-regulation of BCL-XL 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 NFkappaB signaling pathway to up-regulate BCL-XL 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.
Tran
Nhan L
NL
Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
McDonough
Wendy S
WS
Savitch
Benjamin A
BA
Sawyer
Thomas F
TF
Winkles
Jeffrey A
JA
Berens
Michael E
ME
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001254:Astrocytoma; D001932:Brain Neoplasms; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D000074049:Cytokine TWEAK; D003603:Cytotoxins / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008024:Ligands; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; D051020:bcl-X Protein
D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C491073:BCL2L2 protein, human; D002352:Carrier Proteins; D000074049:Cytokine TWEAK; D003603:Cytotoxins; D020672:I-kappa B Proteins; D008024:Ligands; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha