Engels Ingo H, Totzke Gudrun, Fischer Ute, Schulze-Osthoff Klaus, Jänicke Reiner U
Institute of Molecular Medicine, University of Düsseldorf, Building 23.12, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
Mol Cell Biol. 2005 Apr;25(7):2808-18. doi: 10.1128/MCB.25.7.2808-2818.2005.
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.
尽管死亡受体信号传导涉及将共同组分募集到其死亡诱导信号复合物（DISC）中，但各种肿瘤细胞对每个单独受体的凋亡敏感性差异很大。最近研究表明，除了半胱天冬酶 - 8外，半胱天冬酶 - 10也被募集到DISC中，但其在死亡受体信号传导中的功能仍不清楚。在这里，我们表明半胱天冬酶 - 10的表达使MCF - 7乳腺癌细胞对TRAIL诱导的凋亡敏感，但对肿瘤坏死因子（TNF）诱导的凋亡不敏感。这种敏感性在低TRAIL浓度下或在早期时间点评估凋亡时最为明显。半胱天冬酶 - 10介导的对TRAIL诱导凋亡的敏感性似乎依赖于半胱天冬酶 - 3，因为在MCF - 7 / casp - 3细胞中而非在缺乏半胱天冬酶 - 3的MCF - 7细胞中表达半胱天冬酶 - 10可克服TRAIL抗性。有趣的是，TRAIL受体2（TRAIL - R2）而非TRAIL - R1的中和以半胱天冬酶 - 10依赖性方式损害凋亡，表明半胱天冬酶 - 10增强TRAIL - R2诱导的细胞死亡。此外，虽然在TNF处理的细胞中半胱天冬酶 - 10的加工延迟，但TRAIL触发了半胱天冬酶 - 10和 - 3的非常快速的激活。因此，我们提出了一个模型，其中半胱天冬酶 - 10是TRAIL介导的凋亡过程中的关键组分，此外还积极需要半胱天冬酶 - 3。这在仅提供不足以使半胱天冬酶 - 8快速募集到DISC的低TRAIL浓度的系统中可能特别重要。
