title: An NF-κB p65-cIAP2 link is necessary for mediating resistance to TNF-α induced cell death in gliomas.
abstract: Malignant gliomas are diffusively infiltrative and remain among the deadliest of all cancers. NF-κB is a transcription factor that mediates cell growth, migration and invasion, angiogenesis and resistance to apoptosis. Normally, the activity of NF-κB is tightly regulated by numerous mechanisms. However, in many cancers, NF-κB is constitutively activated and may function as a tumor promoter. Herein, we show that in gliomas, NF-κB is constitutively activated and the levels of cIAP2, Bcl-2, Bcl-xL and Survivin are elevated. These genes are regulated by NF-κB and can inhibit apoptosis. To understand the potential role of NF-κB p65 in suppressing apoptosis, we generated human glioma cell lines that inducibly express shRNA molecules specific for p65. We demonstrate that in the absence of p65, TNF-α induced cIAP2 expression is significantly reduced while the levels of Bcl-2, Bcl-xL and Survivin are not affected. These data suggest that of these genes, only cIAP2 is a direct target of p65, which was confirmed using RT-PCR and chromatin immunoprecipitation (ChIP) assays. By reducing the levels of p65 and/or cIAP2 levels, we demonstrate that the levels of RIP poly-ubiquitination are reduced, and that p65-deficient glioma cells are more sensitive to the cytotoxic effects of TNF-α. Specifically, in the presence of TNF-α glioma cells lacking p65 and/or cIAP2 showed cellular proliferation defects and underwent cell death. These data suggest that NF-κB and/or cIAP2 may be therapeutically relevant targets for the treatment of malignant gliomas.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, 1918 University Blvd, MCLM 310, Birmingham, AL 35294-0005, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Zhao
authors.forename: Travis
authors.initials: T
authors.lastname: Laver
authors.forename: Suk W
authors.initials: SW
authors.lastname: Hong
authors.forename: George B
authors.initials: GB
authors.lastname: Twitty
authors.forename: Annelies
authors.initials: A
authors.lastname: Devos
authors.forename: Marijke
authors.initials: M
authors.lastname: Devos
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
authors.forename: Susan E
authors.initials: SE
authors.lastname: Nozell
mesh_terms: D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001932:Brain Neoplasms / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000473:pathology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D020169:Caspases