Caspase-10 sensitizes breast carcinoma cells to TRAIL-induced but not tumor necrosis factor-induced apoptosis in a caspase-3-dependent manner.
Although signaling by death receptors involves the recruitment of common components into their death-inducing signaling complexes (DISCs), apoptosis susceptibility of various tumor cells to each individual receptor differs quite dramatically. Recently it was shown that, besides caspase-8, caspase-10 is also recruited to the DISCs, but its function in death receptor signaling remains unknown. Here we show that expression of caspase-10 sensitizes MCF-7 breast carcinoma cells to TRAIL- but not tumor necrosis factor (TNF)-induced apoptosis. This sensitization is most obvious at low TRAIL concentrations or when apoptosis is assessed at early time points. Caspase-10-mediated sensitization for TRAIL-induced apoptosis appears to be dependent on caspase-3, as expression of caspase-10 in MCF-7/casp-3 cells but not in caspase-3-deficient MCF-7 cells overcomes TRAIL resistance. Interestingly, neutralization of TRAIL receptor 2 (TRAIL-R2), but not TRAIL-R1, impaired apoptosis in a caspase-10-dependent manner, indicating that caspase-10 enhances TRAIL-R2-induced cell death. Furthermore, whereas processing of caspase-10 was delayed in TNF-treated cells, TRAIL triggered a very rapid activation of caspase-10 and -3. Therefore, we propose a model in which caspase-10 is a crucial component during TRAIL-mediated apoptosis that in addition actively requires caspase-3. This might be especially important in systems where only low TRAIL concentrations are supplied that are not sufficient for the fast recruitment of caspase-8 to the DISC.
Engels
Ingo H
IH
Institute of Molecular Medicine, University of Düsseldorf, Building 23.12, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
Totzke
Gudrun
G
Fischer
Ute
U
Schulze-Osthoff
Klaus
K
Jänicke
Reiner U
RU
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D053455:Caspase 10; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048069:Tumor Necrosis Factors / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053455:Caspase 10; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases; C506438:CASP10 protein, human