Dumitru Claudia Alexandra, Carpinteiro Alexander, Trarbach Tanja, Hengge Ulrich R, Gulbins Erich
Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
Apoptosis. 2007 Aug;12(8):1533-41. doi: 10.1007/s10495-007-0081-9.
Previous studies indicated that signalling via CD95 and DR5 is greatly enhanced by the formation of ceramide-enriched membrane platforms. Here, we employed this concept to convert doses of subtherapeutic TRAIL that were unable to release ceramide and kill leukemic B-cells or ex vivo T lymphocytes, into a very effective apoptotic stimulus. Ceramide production was induced by application of sub-toxic doses of doxorubicin that resulted in an activation of the acid sphingomyelinase (ASM), release of ceramide and formation of ceramide-enriched membrane platforms. The latter served DR5 to cluster after application of very low doses of TRAIL in combination with doxorubicin. Genetic deficiency of the ASM abrogated doxorubicin-induced ceramide release, as well as clustering of DR5 and apoptosis induced by the combined treatment of doxorubicin and TRAIL. These data show that local release of ceramide potentiates very low, otherwise inactive doses of TRAIL that may represent a novel therapeutic concept to treat tumors.
先前的研究表明，通过富含神经酰胺的膜平台的形成，经由CD95和DR5的信号传导会大大增强。在此，我们运用这一概念，将无法释放神经酰胺且不能杀死白血病B细胞或离体T淋巴细胞的亚治疗剂量的肿瘤坏死因子相关凋亡诱导配体（TRAIL），转化为一种非常有效的凋亡刺激物。通过应用亚毒性剂量的阿霉素诱导神经酰胺生成，这导致酸性鞘磷脂酶（ASM）激活、神经酰胺释放以及富含神经酰胺的膜平台形成。在应用极低剂量的TRAIL与阿霉素联合使用后，后者促使DR5聚集。ASM的基因缺陷消除了阿霉素诱导的神经酰胺释放，以及DR5聚集和阿霉素与TRAIL联合治疗诱导的凋亡。这些数据表明，神经酰胺的局部释放增强了极低剂量、原本无活性的TRAIL，这可能代表了一种治疗肿瘤的新治疗概念。
