Unknown

Dataset Information

0

MUC16 mucin (CA125) attenuates TRAIL-induced apoptosis by decreasing TRAIL receptor R2 expression and increasing c-FLIP expression.


ABSTRACT: BACKGROUND:MUC16 (CA125) is a large transmembrane mucin protein (> 200 kDa) aberrantly expressed in approximately 80% of human epithelial ovarian cancers (EOC). MUC16 expression in EOC cells is associated with increased tumorigenesis and inhibiton of genotoxic drug-induced apoptosis. However, the mechanism by which MUC16 mediates these effects is unknown. In the present study, we investigated the mechanisms by which MUC16 attenuates TRAIL-induced apoptosis. METHODS:MUC16 expression was down-regulated by stably expressing an anti-MUC16 single-chain antibody (scFv) targeted to the endoplasmic reticulum (ER), which prevents cell surface localization of MUC16 in OVCAR3 cells. We also generated a MUC16 C-terminal domain (MUC16CTD) construct that was stably expressed in MUC16 negative SKOV3 cells. RESULTS:We show that MUC16 attenuates apoptosis, activation of caspase-8 and mitochondria activation in EOC cells in response to TRAIL. MUC16 decreases TRAIL receptor R2 (DR5) expression and inhibits pro-caspase-8 activation at the death-inducing signaling complex (DISC). MUC16CTD expression is sufficient to attenuate the TRAIL signaling cascade. MUC16 knockdown decreases caspase-8 inhibitor cFLIP mRNA levels, increases cFLIP degradation, and consequently increases TRAIL-induced apoptosis. Down-regulation of cFLIP following treatment of MUC16-expressing OVCAR3 cells with cFLIP siRNA also increases TRAIL-induced apoptosis. CONCLUSIONS:These findings indicate that MUC16 protects EOC cells against TRAIL-induced apoptosis through multiple mechanisms including the blockade of TRAIL R2 expression and the regulation of cFLIP expression at both the transcriptional and the protein level.

SUBMITTER: Matte I 

PROVIDER: S-EPMC4234371 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

MUC16 mucin (CA125) attenuates TRAIL-induced apoptosis by decreasing TRAIL receptor R2 expression and increasing c-FLIP expression.

Matte Isabelle I   Lane Denis D   Boivin Marianne M   Rancourt Claudine C   Piché Alain A  

BMC cancer 20140401


<h4>Background</h4>MUC16 (CA125) is a large transmembrane mucin protein (> 200 kDa) aberrantly expressed in approximately 80% of human epithelial ovarian cancers (EOC). MUC16 expression in EOC cells is associated with increased tumorigenesis and inhibiton of genotoxic drug-induced apoptosis. However, the mechanism by which MUC16 mediates these effects is unknown. In the present study, we investigated the mechanisms by which MUC16 attenuates TRAIL-induced apoptosis.<h4>Methods</h4>MUC16 expressio  ...[more]

Similar Datasets

| S-EPMC2635045 | biostudies-literature
| S-EPMC7429845 | biostudies-literature
| S-EPMC7054686 | biostudies-literature
| S-EPMC4429113 | biostudies-literature
| S-EPMC2650410 | biostudies-literature
| S-EPMC9563928 | biostudies-literature
| S-EPMC4046138 | biostudies-literature
| S-EPMC3191303 | biostudies-literature
| S-EPMC1170170 | biostudies-other
| S-EPMC4651718 | biostudies-literature