Search results for "casp8"
showing 10 items of 19 documents
Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation.
2017
Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP−/−) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in h…
Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4
2008
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 antia…
NF-κB protects Behçet's disease T cells against CD95-induced apoptosis up-regulating antiapoptotic proteins
2005
Objective To determine whether prolongation of the inflammatory reaction in patients with Behcet's disease (BD) is related to apoptosis resistance and is associated with the up-regulation of antiapoptotic factors. Methods The percentage of cell death was evaluated by flow cytometry in peripheral blood mononuclear cells from 35 patients with BD and 30 healthy volunteers. The expression levels of antiapoptotic factors and NF-κB regulatory proteins were measured using Western blotting and immunohistochemical analyses. To down-regulate NF-κB nuclear translocation, BD T lymphocytes were exposed in vitro to thalidomide and subjected to transfection with NF-κB small interfering RNA. Results Althou…
Control of target cell survival in thyroid autoimmunity by T helper cytokines via regulation of apoptotic proteins
2000
After autoimmune inflammation, interactions between CD95 and its ligand (CD95L) mediate thyrocyte destruction in Hashimoto's thyroiditis (HT). Conversely, thyroid autoimmune processes that lead to Graves' disease (GD) result in autoantibody-mediated thyrotropin receptor stimulation without thyrocyte depletion. We found that GD thyrocytes expressed CD95 and CD95L in a similar manner to HT thyrocytes, but did not undergo CD95-induced apoptosis either in vivo or in vitro. This pattern was due to the differential production of TH1 and TH2 cytokines. Interferon gamma promoted caspase up-regulation and CD95-induced apoptosis in HT thyrocytes, whereas interleukin 4 and interleukin 10 protected GD …
Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95-and TRAIL receptor-mediated apo…
2005
Hepatocellular carcinoma (HCC) is highly resistant to chemotherapy, leading to a poor prognosis of advanced disease. Inhibitors of histone deacetylase (HDACi) induce re-differentiation in tumor cells and thereby re-establish sensitivity towards apoptotic stimuli. HDACi are entering the clinical stage of tumor treatment, and several substances are currently being tested in clinical trials to prove their efficacy in the treatment of leukemias and solid tumors. In this study, we investigated the impact of the HDACi valproic acid (VA) on TRAIL- and CD95-mediated apoptosis in hepatoma cells, as well as its sensitizing effect on a chemotherapeutic agent. Treatment of HepG2 cells with VA increased…
Parthenolide generates reactive oxygen species and autophagy in MDA-MB231 cells. A soluble parthenolide analogue inhibits tumour growth and metastasi…
2013
Triple-negative breast cancers (TNBCs) are clinically aggressive forms associated with a poor prognosis. We evaluated the cytotoxic effect exerted on triple-negative MDA-MB231 breast cancer cells both by parthenolide and its soluble analogue dimethylamino parthenolide (DMAPT) and explored the underlying molecular mechanism. The drugs induced a dose- and time-dependent decrement in cell viability, which was not prevented by the caspase inhibitor z-VAD-fmk. In particular in the first hours of treatment (1–3 h), parthenolide and DMAPT strongly stimulated reactive oxygen species (ROS) generation. The drugs induced production of superoxide anion by activating NADPH oxidase. ROS generation caused…
Autocrine production of interleukin-4 and interleukin-10 is required for survival and growth of thyroid cancer cells.
2006
AbstractAlthough CD95 and its ligand are expressed in thyroid cancer, the tumor cell mass does not seem to be affected by such expression. We have recently shown that thyroid carcinomas produce interleukin (IL)-4 and IL-10, which promote resistance to chemotherapy through the up-regulation of Bcl-xL. Here, we show that freshly purified thyroid cancer cells were completely refractory to CD95-induced apoptosis despite the consistent expression of Fas-associated death domain and caspase-8. The analysis of potential molecules able to prevent caspase-8 activation in thyroid cancer cells revealed a remarkable up-regulation of cellular FLIPL (cFLIPL) and PED/PEA-15, two antiapoptotic proteins whos…
The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL…
2009
Abstract This paper shows that the histone deacetylase inhibitor SAHA sensitised at sub-toxic doses human hepatocellular carcinoma cells (HepG2, Hep3B and SK-Hep1) to TRAIL-induced apoptosis, while it was ineffective in primary human hepatocytes (PHHs). In particular in HCC cells SAHA increased the expression of death receptor 5 (DR5) and caused a decrement of c-Flip. These two modifications provoked in the presence of TRAIL the rapid production of TRAIL-DISC and the activation of caspase-8. Consequently SAHA/TRAIL combination induced many apoptotic events, such as a cleavage of Bid into tBid, dissipation of mitochondrial membrane potential, activation of caspase-3 with the consequent cleav…
Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.
2014
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regressionmodels adjusting for stud…
cFLIPL Inhibits Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated NF-κB Activation at the Death-inducing Signaling Complex in Human Ke…
2004
Human keratinocytes undergo apoptosis following treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via surface-expressed TRAIL receptors 1 and 2. In addition, TRAIL triggers nonapoptotic signaling pathways including activation of the transcription factor NF-kappaB, in particular when TRAIL-induced apoptosis is blocked. The intracellular protein cFLIP(L) interferes with TRAIL-induced apoptosis at the death-inducing signaling complex (DISC) in many cell types. To study the role of cFLIP(L) in TRAIL signaling, we established stable HaCaT keratinocyte cell lines expressing varying levels of cFLIP(L). Functional analysis revealed that relative cFLIP(L) levels correlat…