2007
DOI: 10.1016/j.ccr.2007.08.029
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Autocrine TNFα Signaling Renders Human Cancer Cells Susceptible to Smac-Mimetic-Induced Apoptosis

Abstract: A small-molecule mimetic of Smac/Diablo that specifically counters the apoptosis-inhibiting activity of IAP proteins has been shown to enhance apoptosis induced by cell surface death receptors as well as chemotherapeutic drugs. Survey of a panel of 50 human non-small-cell lung cancer cell lines has revealed, surprisingly, that roughly one-quarter of these lines are sensitive to the treatment of Smac mimetic alone, suggesting that an apoptotic signal has been turned on in these cells and is held in check by IAP… Show more

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Cited by 540 publications
(723 citation statements)
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“…35,36,44 This conclusion is supported by the following lines of evidence: First, the TNFacatching antibody Enbrel fails to prevent BV6-induced cell death in primary CLL cells. Similarly, we recently described that BV6/Dexamethasone-induced cell death in childhood ALL occurs in a TNFa-independent manner.…”
Section: Discussionmentioning
confidence: 79%
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“…35,36,44 This conclusion is supported by the following lines of evidence: First, the TNFacatching antibody Enbrel fails to prevent BV6-induced cell death in primary CLL cells. Similarly, we recently described that BV6/Dexamethasone-induced cell death in childhood ALL occurs in a TNFa-independent manner.…”
Section: Discussionmentioning
confidence: 79%
“…Mean and SEM of 18 individual CLL samples measured in duplicate or triplicate (samples no. 2,6,8,15,17,18,19,21,24,28,33,36,39,40,41,43,48,50) are shown; **p < 0.001; *p < 0.05; (right) Graph illustrates specific cell death upon treatment with 10 mM Fludarabine or BV6 of genomic subgroups including norm/13q-, IGVH non-mutated, tp53 mutated and 17p deletion. (e and f) BV6-sensitive primary CLL cells were co-treated with 10 mM BV6 and 1,000 ng/ml CD40 ligand (e) or stimulated with BV6 in normal or conditioned medium at indicated concentrations (f) for 48 hr.…”
Section: Bv6 Induces Cell Death In Primary Cll Cells Irrespective Of mentioning
confidence: 99%
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“…Previous studies reported that, at least in certain cell types, Tweak-and SM-induced cell death relied on the NIK-dependent neosynthesis of endogenous TNFα via induction of the classical and/or the alternative NF-κB pathway. 11,26,27,33 We can rule out this possibility in our in vitro and in vivo genetic models. Indeed, we showed that Tweak-, LTβR agonist-or SM-induced NIK stabilization in MEFs is by itself not sufficient to induce cell death and that NIK deficiency protected the MEFs from TNFR1-mediated death induced by exogenous TNFα.…”
Section: Discussionmentioning
confidence: 99%
“…[21][22][23][24][25] Synthetic small molecules mimicking Smac (Smac mimetics (SMs)) emerged as tools to induce c-IAP1/2 depletion and were consequently shown to sensitize particular cancer cell lines to TNFR1-mediated RIP1-dependent death. 11,[26][27][28] Apart from these chemicals, a set of biological ligand of the TNF family, such as lymphotoxin LTα 1 β 2 , CD40L or Tweak, also appeared to target c-IAP1/2 toward the proteasomal and/ or lysosomal degradative pathways. [29][30][31][32][33][34] c-IAP1/2 depletion leads to NIK (NF-κB-inducing kinase) stabilization and the phosphorylation of both IKKα and NF-κB2/p100 prior to the processing of p100 into p52, a pathway defined as the alternative, or non-canonical, NF-κB pathway.…”
mentioning
confidence: 99%