Doxorubicin enhances TRAIL-induced cell death via ceramide-enriched membrane platforms
- 23 May 2007
- journal article
- research article
- Published by Springer Science and Business Media LLC in Apoptosis
- Vol. 12 (8), 1533-1541
- https://doi.org/10.1007/s10495-007-0081-9
Abstract
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.Keywords
This publication has 58 references indexed in Scilit:
- The clinical trail of TRAILEuropean Journal Of Cancer, 2006
- CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell deathNature, 2005
- NK Cell TRAIL Eliminates Immature Dendritic Cells In Vivo and Limits Dendritic Cell Vaccination EfficacyPublished by The American Association of Immunologists ,2004
- TRAIL/Apo-2 Ligand Induces Primary Plasma Cell ApoptosisThe Journal of Immunology, 2002
- Mechanisms involved in development of resistance to adenovirus-mediated proapoptotic gene therapy in DLD1 human colon cancer cell lineGene Therapy, 2002
- TRAIL Receptors 1 (DR4) and 2 (DR5) Signal FADD-Dependent Apoptosis and Activate NF-κBImmunity, 1997
- Control of TRAIL-Induced Apoptosis by a Family of Signaling and Decoy ReceptorsScience, 1997
- An Antagonist Decoy Receptor and a Death Domain-Containing Receptor for TRAILScience, 1997
- The Receptor for the Cytotoxic Ligand TRAILScience, 1997
- Identification and characterization of a new member of the TNF family that induces apoptosisImmunity, 1995