IKK1/2 protect human cells from TNF-mediated RIPK1-dependent apoptosis in an NF-κB-independent manner
| Autor: | Christian Kaltschmidt, Carsten Slotta, Barbara Kaltschmidt, Johannes F. W. Greiner, Nina Pfisterer, Svenja Kleinwächter, Lucia M. Ruiz-Perera, Elena Henkel, Jonathan Storm, Maren Pieper |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cell death Programmed cell death RIPK1 Tumor necrosis factor Apoptosis IκB kinase 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Annexin Humans Molecular Biology poptosis IKK Tumor Necrosis Factor-alpha NF-kappa B NF-κB Cell Biology NFKB1 I-kappa B Kinase 030104 developmental biology NF-kappa-B HEK293 Cells chemistry 030220 oncology & carcinogenesis Receptor-Interacting Protein Serine-Threonine Kinases Cancer research Tumor necrosis factor alpha CRISPR-Cas Systems Signal Transduction |
| Zdroj: | Biochimica et biophysica acta. Molecular cell research. 1865(8) |
| ISSN: | 0167-4889 |
| Popis: | TNF signaling is directly linked to cancer development and progression. A broad range of tumor cells is able to evade cell death induced by TNF impairing the potential anti-cancer value of TNF in therapy. Although sensitizing cells to TNF-induced death therefore has great clinical implications, detailed mechanistic insights into TNF-mediated human cell death still remain unknown. Here, we analyzed human cells by applying CRISPR/Cas9n to generate cells deficient of IKK1, IKK2, IKK1/2 and RELA. Despite stimulation with TNF resulted in impaired NF-κB activation in all genotypes compared to wildtype cells, increased cell death was observable only in IKK1/2-double-deficient cells. Cell death could be detected by Caspase-3 activation and binding of Annexin V. TNF-induced programmed cell death in IKK1/2-/- cells was further shown to be mediated via RIPK1 in a predominantly apoptotic manner. Our findings demonstrate the IKK complex to protect from TNF-induced cell death in human cells independently to NF-κB RelA suggesting IKK1/2 to be highly promising targets for cancer therapy. |
| Databáze: | OpenAIRE |
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