NF-κB activation fails to protect cells to TNFα-induced apoptosis in the absence of Bcl-x<inf>L</inf>, But not Mcl-1, Bcl-2 or Bcl-w

Elisenda Casanelles, Raffaella Gozzelino, Fernando Marqués-Fernández, Victoria Iglesias-Guimarais, Mercè Garcia-Belinchón, María Sánchez-Osuna, Carme Solé, Rana S. Moubarak, Joan X. Comella, Victor J. Yuste

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10 Citations (Scopus)

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-xL, 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-xL-downregulated cells from TNFα-induced cell death, meaning that TNFα is not able to promote cell survival in the absence of Bcl-xL. In addition, Bcl-xL 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-xL. We have corroborated these findings using RD and DU-145 cells, which also become sensitive to TNFα-induced apoptosis after Bcl-xL knockdown despite that NF-κB remains activated. Altogether, our results point out that the impairment of the anti-apoptotic function of Bcl-xL should make cells sensitive towards external insults circumventing the TNFα-triggered NF-κB-mediated cytoprotective effect. Hence, the specific inhibition of Bcl-xL could be envisaged as a promising alternative strategy against NF-κB-dependent highly chemoresistant proliferative malignancies. © 2013 Elsevier B.V.
Original languageEnglish
Pages (from-to)1085-1095
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
DOIs
Publication statusPublished - 1 May 2013

Keywords

  • Apoptosis
  • Bcl-2 family
  • Bcl-x L
  • NF-κB
  • TNFα

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