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Resistance to the cytotoxic effects of tumor necrosis factor alpha can be overcome by inhibition of a FADD/caspase-dependent signaling pathway

Khwaja, A; Tatton, L; (1999) Resistance to the cytotoxic effects of tumor necrosis factor alpha can be overcome by inhibition of a FADD/caspase-dependent signaling pathway. J BIOL CHEM , 274 (51) 36817 - 36823. Gold open access

Abstract

Tumor necrosis factor (TNF) alpha initiates the activation of a pro-apoptotic pathway involving the recruitment of the death domain containing protein FADD and the subsequent activation of specific proteases (caspases). Many cells are resistant, however, to the cytotoxic effects of TNF alpha due to the concurrent activation of pro-survival pathways involving the transcription factor NP kappa B and TRAF2. Here we show that the TNF alpha-activated FADD/caspase pathway can also exert an unexpected pro-survival effect. Inhibition of this pathway in NIH3T3 fibroblasts or U937 leukemic cells by peptide caspase inhibitors or expression of dominant-negative FADD leads to rapid death following treatment with TNF alpha, whereas control cells are TNF alpha-resistant. FADD/caspase inhibited cells die by a non-apoptotic mechanism caused by increased production of reactive oxygen species which precedes loss of the mitochondrial membrane potential. Cytotoxicity can be prevented by preincubation with antioxidants including reduced glutathione or by expression of a dominant-negative Rac GTP-binding protein. These results indicate that caspase activation in response to TNF alpha as anti-necrotic as well as pro-apoptotic effects and extend our understanding of the biological role of these proteases.

Type: Article
Title: Resistance to the cytotoxic effects of tumor necrosis factor alpha can be overcome by inhibition of a FADD/caspase-dependent signaling pathway
Open access status: An open access publication
Publisher version: http://www.jbc.org/content/early/recent/0
Keywords: NF-KAPPA-B, CELL-DEATH INDUCTION, INDUCED APOPTOSIS, TNF-ALPHA, PERMEABILITY TRANSITION, SUPEROXIDE-DISMUTASE, TRANSCRIPTION FACTOR, CD95 FAS/APO-1, ACTIVATION, PROTEIN
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/154662
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