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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Gozzelino, Raffaella Moubarak, Rana S. Casanelles, Elisenda Yuste, Victor J. Sánchez-osuna, María Solé, Carme Iglesias-guimarais, Victoria Comella, Joan X. Marqués-fernández, Fernando Garcia-belinchón, Mercè |
| Description | Author Affiliation: Casanelles E ( Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain.) |
| Abstract | TNFα can promote either cell survival or cell death. The activation of NF-κB plays a central role in cell survival while its inhibition makes TNFα-triggered cytotoxicity possible. Here, we report that the overexpression of a non-degradable mutant of the inhibitor of NF-κB (super-repressor (SR)-IκBα) sensitizes HeLa cells towards TNFα-induced apoptosis, involving caspases activation and cytocrome C release from the mitochondria. Interestingly, we describe that the specific knockdown of Bcl-x $_{L}$ , but not that of Bcl-2, Bcl-w or Mcl-1, renders cells sensitive to TNFα-induced apoptosis. This cytotoxic effect occurs without altering the activation of NF-κB. Then, the activation of the NF-κB pathway is not sufficient to protect Bcl-x $_{L}$ -downregulated cells from TNFα-induced cell death, meaning that TNFα is not able to promote cell survival in the absence of Bcl-x $_{L}$ . In addition, Bcl-x $_{L}$ silencing does not potentiate the cytotoxicity afforded by the cytokine in SR-IκBα-overexpressing cells. This indicates that TNFα-induced apoptosis in SR-IκBα-overexpressing cells relies on the protein levels of Bcl-x $_{L}$ . We have corroborated these findings using RD and DU-145 cells, which also become sensitive to TNFα-induced apoptosis after Bcl-x $_{L}$ knockdown despite that NF-κB remains activated. Altogether, our results point out that the impairment of the anti-apoptotic function of Bcl-x $_{L}$ should make cells sensitive towards external insults circumventing the TNFα-triggered NF-κB-mediated cytoprotective effect. Hence, the specific inhibition of Bcl-x $_{L}$ could be envisaged as a promising alternative strategy against NF-κB-dependent highly chemoresistant proliferative malignancies. |
| ISSN | 00063002 |
| Journal | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |
| Issue Number | 5 |
| Volume Number | 1833 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2013-05-01 |
| Publisher Place | Netherlands |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Regulatory Proteins Proto-Oncogene Proteins C-bcl-2 Tumor Necrosis Factor-alpha Metabolism Bcl-X Protein Apoptosis Genetics Cell Survival Drug Effects Gene Expression Regulation, Neoplastic Gene Silencing HeLa Cells I-kappa B Proteins Pharmacology Mitochondria Myeloid Cell Leukemia Sequence 1 Protein NF-kappa B Antagonists & Inhibitors Research Support, Non-U.S. Gov't Biochemistry |
| Content Type | Text |
| Resource Type | Article |
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