Resistance to CD95-mediated apoptosis through constitutive c-FLIP expression in a non-Hodgkin's lymphoma B cell line

Irisarri, Magdalena; Plumas, Joël; Bonnefoix, Thierry; Jacob, Marie Christine; Roucard, Corinne; Ma, Pasquier; Jj, Sotto; Lajmanovich, Alicia

doi:10.1038/sj.leu.2401954

Cited by 47 publications

(31 citation statements)

References 60 publications

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“…[1][2][3] The death ligand TRAIL (Apo2L) has been shown to specifically induce apoptosis in many tumor cell lines while sparing most normal cells. 4 Similar to CD95 (Fas/APO-1), binding of TRAIL receptor 1 (TRAIL-R1/DR4) and TRAIL-R2 (Apo2, DR5, KILLER and TRICK2) by its ligand induces receptor clustering and formation of the death-inducing signaling complex (DISC).…”

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confidence: 99%

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

et al. 2008

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We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify that primary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED, cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of these antiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted in a significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosis induction by TRAIL and chemotherapy via downregulation of the antiapoptotic factors PED, cFLIP, Bcl-xL and Bcl-2. Furthermore, we provide evidence that exogenous IL-4 was able to upregulate the expression levels of these antiapoptotic proteins and potently stabilized the growth of normal epithelial cells rendering them apoptosis resistant. In conclusion, IL-4 acts as an autocrine survival factor in epithelial cells. Our results indicate that inhibition of IL-4/IL-4R signaling may serve as a novel treatment for epithelial cancers.

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confidence: 99%

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

et al. 2008

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“…126 Another mechanism for cellular resistance towards death receptor-induced apoptosis is the activation of survival signaling pathways, for instance via upregulation of NF-B or members of the IAP family or FLIP proteins. 127 Other possible causes include the deregulation of the mitochondrial apoptosome, 67 especially the members of the Bcl-2 family which may show considerable intra-and interdisease variability, eg in lymphoma, 128 and may shift to an apoptosis-refractory profile when resistance develops. 129 Recently, an IAP-neutralizing and therefore apoptosis-promoting mitochondrial protein, termed Leukemia Smac/Diablo, has been identified that obviously plays a critical role in antagonizing the caspase-inhibitory effect of IAPs.…”

Section: Death Ligands In Cancer Therapymentioning

confidence: 99%

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

et al. 2001

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“…The activation of NF-kB has been shown to induce the expression of apoptosis-protecting proteins like IAP (inhibitors of apoptosis), TRAF2 and FLIP (Wang et al, 1998;Micheau et al, 2001). Constitutive downregulation of caspase-8 or the overexpression of FLIP represent other protective mechanisms preventing an efficient DISC formation (Irmler et al, 1997;Irisarri et al, 2000;Eggert et al, 2001;Fulda et al, 2001). For type II cells it has been shown that both overexpression of Bcl-x L (Hinz et al, 2000) and induction of PKC by PMA (Scaffidi et al, 1999) are able to inhibit the cytochrome C release thus preventing the activation of caspase-9 and caspase-3.…”

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Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells

et al. 2003

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Inability to die by apoptosis is one of the reasons for the deregulated growth of tumour cells and the frequently observed failure of chemotherapy. In this study we thought to identify the common and functionally important characteristics responsible for the apoptosis resistance of pancreatic tumour cells. We analysed cell surface expression level of death receptors CD95 and TRAIL-R1-4 as well as the expression profile of sixteen apoptosis-relevant proteins in five pancreatic carcinoma cell lines Capan1, Colo357, PancTuI, Panc89 and Panc1. These data were evaluated in the context of sensitivity towards anti-CD95 and TRAIL-mediated apoptosis. Here we report that except for resistant Panc1 cells, which only marginally expressed CD95, all other cell lines showed comparable levels of CD95 and TRAIL receptors irrespectively of their apoptotic phenotype. Interestingly, we found that the elevated expression of FLIP, Bcl-x L and IAP in parallel with a downregulation of FADD and Bid was common for the resistant cell lines. Consequently, stable overexpression of XIAP, Bcl-x L or dominant negative FADD in sensitive cells significantly reduced the death receptor mediated apoptosis while the overexpression of Bid rendered the resistant cells sensitive.

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Resistance to CD95-mediated apoptosis through constitutive c-FLIP expression in a non-Hodgkin's lymphoma B cell line

Cited by 47 publications

References 60 publications

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells

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