Targeting A20 enhances TRAIL-induced apoptosis in hepatocellular carcinoma cells
ABSTRACT A20 was initially identified as a primary gene product following TNF α treatment in human umbilical vein endothelial cells. Increased A20 expression is associated with tumorigenesis in many cancers, whereas the loss of A20 function is linked to lymphoma. It has been reported that A20 protects cells from TRAIL-induced apoptosis; however, the mechanism by which A20 is involved is still largely unknown. Our results indicate that TRAIL induces the hepatocellular carcinoma apoptosis associated with A20 knockdown in a concentration-dependent manner. TRAIL-induced apoptosis requires p18 caspase-8 activation, and, the activation of caspase-8 is at least in part, due to the direct cleavage of RIP1 by A20 knockdown. These findings suggest that A20 modulates the sensitivity to TRAIL by RIP1 ubiquitination, thereby repressing the recruitment and activation of pro-caspase-8 into the active form caspase-8. Thus, our study suggests that A20 protects against TRAIL-induced apoptosis through the regulation of RIP1 ubiquitination.
- SourceAvailable from: Feng WeiBiochemical and Biophysical Research Communications 04/2012; 420(2):485. DOI:10.1016/j.bbrc.2012.03.044 · 2.28 Impact Factor
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ABSTRACT: Abstract We analyzed clinicopathologic implication of A20/Tumor necrosis factor alpha-induced protein 3 deletion in diffuse large B-cell lymphoma (DLBCL) using fluorescence in situ hybridization, according to germinal center B-cell (GCB) vs. non-GCB/activated B-cell (ABC) phenotypes and rituximab treatment. Excluding primary CNS and EBV-positive lymphomas, 134 DLBCLs were analyzed. A20 was deleted in 23.1% (31/134) of DLBCLs containing 21.6% (29/134) of monoallelic and 1.5% (2/134) of biallelic deletion with no predilection for GCB vs. non-GCB/ABC. In univariate analysis, A20 deletion was marginally associated with good prognosis in rituximab-treated subgroup (n=109; p=0.0454), non-gastrointestinal lymphoma (n=108; p=0.0320) and nodal lymphoma (n=46; p=0.0411). In multivariate analysis in rituximab-treated DLBCL, MUM1 and international prognostic index (IPI) were independent prognostic factors (p=0.021 [IPI]; p=009 [MUM1]) with a marginal good prognostic effect for A20 deletion (p=0.047). Taken together, A20 deletion was observed in similar frequencies in GCB and non-GCB/ABC, and was not a poor prognostic factor in DLBCL.Leukemia & lymphoma 01/2013; 54(9). DOI:10.3109/10428194.2012.762511 · 2.89 Impact Factor
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ABSTRACT: To investigate the effects of the nitrous oxide (NO)-donor sodium nitroprusside (SNP) on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human gastric cancer cells. The MTT assay and flow cytometry were used to detect cellular proliferation and markers of apoptosis, respectively. Expression levels of caspases-8, and 9 were determined by Western blot. Changes in Nitric Oxide Synthase (NOS) activity, NO production, and caspase activation were also evaluated. We found that TRAIL induced apoptosis and cell cycle arrest in human gastric cancer cell lines, and that this effect was mediated by NO production, and activation of both the extrinsic and intrinsic signaling pathways of apoptosis. In addition, we found that the NO-donor SNP sensitizes gastric cancer cells to TRAIL-mediated apoptosis. Treatment of cells with both TRAIL and SNP resulted in increased activation of caspase-8 and caspase-9 and NO release. Inhibition of caspase-8 blocked cell TRAIL-induced apoptosis, while a selective caspase-9 inhibitor was unable to prevent apoptosis induced by either TRAIL or TRAIL plus SNP. Inhibition of NOS could block the activation of caspase-9, but had no obvious effect on cell apoptosis. SNP-sensitized gastric cancer cells to TRAIL-induced cytotoxicity by stimulating the release of NO, in turn facilitating the mitochondria-mediated signal transduction pathway. The engagement of the mitochondria signaling pathways along with the TRAIL death receptor signaling pathway synergistically increase levels of apoptosis in these cells.International immunopharmacology 07/2013; 17(2). DOI:10.1016/j.intimp.2013.06.021 · 2.71 Impact Factor