کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2514152 | 1118452 | 2008 | 11 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: c-FLIP knockdown induces ligand-independent DR5-, FADD-, caspase-8-, and caspase-9-dependent apoptosis in breast cancer cells c-FLIP knockdown induces ligand-independent DR5-, FADD-, caspase-8-, and caspase-9-dependent apoptosis in breast cancer cells](/preview/png/2514152.png)
Cellular-FLICE inhibitory protein (c-FLIP) is an inhibitor of apoptosis downstream of the death receptors Fas, DR4, and DR5, and is expressed as long (c-FLIPL) and short (c-FLIPS) splice forms. We found that the knockdown of c-FLIP using small interfering RNA (siRNA) triggered ligand-independent caspase-8- and -9-dependent spontaneous apoptosis and decreased the proliferation of MCF-7 breast cancer cells. Further analysis revealed that an apoptotic inhibitory complex (AIC) comprised of DR5, FADD, caspase-8, and c-FLIPL exists in MCF-7 cells, and the absence of c-FLIPL from this complex induces DR5- and FADD-mediated caspase-8 activation in the death inducing signaling complex (DISC). c-FLIPS was not detected in the AIC, and using splice form-specific siRNAs we showed that c-FLIPL but not c-FLIPS is required to prevent spontaneous death signaling in MCF-7 cells. These results clearly show that c-FLIPL prevents ligand-independent death signaling and provides direct support for studying c-FLIP as a relevant therapeutic target for breast cancers.
Journal: Biochemical Pharmacology - Volume 76, Issue 12, 15 December 2008, Pages 1694–1704