期刊
JOURNAL OF NEURO-ONCOLOGY
卷 102, 期 3, 页码 367-381出版社
SPRINGER
DOI: 10.1007/s11060-010-0346-y
关键词
NF-kappa B; cIAP2; TNF-alpha; Gliomas; Cell death
资金
- National Cancer Institute [CA-97247, CA-13148-35, CA-13148-31]
- Institute of Neurological Disorders and Stroke [NS-50665]
- UAB Comprehensive Cancer Center [5P30CA013149-38]
- American Cancer Society [IRG-60-001-47]
- Southeastern Brain Tumor Foundation
Malignant gliomas are diffusively infiltrative and remain among the deadliest of all cancers. NF-kappa B is a transcription factor that mediates cell growth, migration and invasion, angiogenesis and resistance to apoptosis. Normally, the activity of NF-kappa B is tightly regulated by numerous mechanisms. However, in many cancers, NF-kappa B is constitutively activated and may function as a tumor promoter. Herein, we show that in gliomas, NF-kappa B is constitutively activated and the levels of cIAP2, Bcl-2, Bcl-xL and Survivin are elevated. These genes are regulated by NF-kappa B and can inhibit apoptosis. To understand the potential role of NF-kappa B 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-alpha 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-alpha. Specifically, in the presence of TNF-alpha glioma cells lacking p65 and/or cIAP2 showed cellular proliferation defects and underwent cell death. These data suggest that NF-kappa B and/or cIAP2 may be therapeutically relevant targets for the treatment of malignant gliomas.
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