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Molecular and Cellular Biology, April 2005, p. 2808-2818, Vol. 25, No. 7
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.7.2808-2818.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Caspase-10 Sensitizes Breast Carcinoma Cells to TRAIL-Induced but Not Tumor Necrosis Factor-Induced Apoptosis in a Caspase- 3-Dependent Manner

Ingo H. Engels,{dagger} Gudrun Totzke, Ute Fischer, Klaus Schulze-Osthoff, and Reiner U. Jänicke*

Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany

Received 23 December 2004/ Accepted 30 December 2004

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.

* Corresponding author. Mailing address: Institute of Molecular Medicine, University of Düsseldorf, Building 23.12, Universitätsstrasse 1, D-40225 Düsseldorf, Germany. Phone: 49-211-8115973. Fax: 49-211-8115892. E-mail: janicke{at}uni-duesseldorf.de.

{dagger} Present address: Genomics Institute of the Novartis Research Foundation, Department of Cancer and Cell Biology, San Diego, CA 92121.

Molecular and Cellular Biology, April 2005, p. 2808-2818, Vol. 25, No. 7
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.7.2808-2818.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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