Article: article from journal or magazin.
Individual caspase-10 isoforms play distinct and opposing roles in the initiation of death receptor-mediated tumour cell apoptosis.
Cell Death and Disease
The cysteine protease caspase-8 is an essential executioner of the death receptor (DR) apoptotic pathway. The physiological function of its homologue caspase-10 remains poorly understood, and the ability of caspase-10 to substitute for caspase-8 in the DR apoptotic pathway is still controversial. Here, we analysed the particular contribution of caspase-10 isoforms to DR-mediated apoptosis in neuroblastoma (NB) cells characterised by their resistance to DR signalling. Silencing of caspase-8 in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-sensitive NB cells resulted in complete resistance to TRAIL, which could be reverted by overexpression of caspase-10A or -10D. Overexpression experiments in various caspase-8-expressing tumour cells also demonstrated that caspase-10A and -10D isoforms strongly increased TRAIL and FasL sensitivity, whereas caspase-10B or -10G had no effect or were weakly anti-apoptotic. Further investigations revealed that the unique C-terminal end of caspase-10B was responsible for its degradation by the ubiquitin-proteasome pathway and for its lack of pro-apoptotic activity compared with caspase-10A and -10D. These data highlight in several tumour cell types, a differential pro- or anti-apoptotic role for the distinct caspase-10 isoforms in DR signalling, which may be relevant for fine tuning of apoptosis initiation.
Amino Acid Motifs, Apoptosis, Caspase 10/chemistry, Caspase 10/genetics, Caspase 8/genetics, Caspase 8/metabolism, Cell Line, Tumor, Humans, Isoenzymes/genetics, Isoenzymes/metabolism, Neuroblastoma/enzymology, Neuroblastoma/genetics, Receptors, Death Domain/genetics, Receptors, Death Domain/metabolism, Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism, TNF-Related Apoptosis-Inducing Ligand/metabolism, Tumor Necrosis Factor-alpha/metabolism
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