Biological Significance of Apoptosis in Ovarian Cancer: TRAIL Therapeutic Targeting

Goncharenko-Khaider, Nadzeya; Lane, Denis; Matte, Isabelle; Rancourt, Claudine; Piché, Alain

doi:10.5772/53380

Cited by 1 publication

(2 citation statements)

References 99 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, OVCAR3 cells endogenously expressing high levels of MUC16 displayed very little pro-caspase-8 processing after incubation with TRAIL for 1 h (Figure 4 D). After initial cleavage of pro-caspase-8 at the DISC, active caspase-8 may directly activate effector caspases such as caspase-3 or may alternatively activate the cleavage and translocation of the pro-apoptotic protein Bid to the mitochondria [ 42 ]. The activation of the mitochondrial apoptotic pathway leads to cytochrome c release, caspase-9 and caspase-3 activation [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…After initial cleavage of pro-caspase-8 at the DISC, active caspase-8 may directly activate effector caspases such as caspase-3 or may alternatively activate the cleavage and translocation of the pro-apoptotic protein Bid to the mitochondria [ 42 ]. The activation of the mitochondrial apoptotic pathway leads to cytochrome c release, caspase-9 and caspase-3 activation [ 42 ]. Kinetic analysis of caspase-9 and caspase-3 activation in OVCAR3 showed that the mitochondrial pathway is activated regardless of the cell’s MUC16 status.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2014

Self Cite

View full text Add to dashboard Cite

BackgroundMUC16 (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.MethodsMUC16 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.ResultsWe 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.ConclusionsThese 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%