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Blockade of death receptor-mediated pathways early in the signaling cascade coincides with distinct apoptosis resistance in cutaneous T-cell lymphoma cells.
- Source :
-
The Journal of investigative dermatology [J Invest Dermatol] 2007 Oct; Vol. 127 (10), pp. 2425-37. Date of Electronic Publication: 2007 May 10. - Publication Year :
- 2007
-
Abstract
- Control of apoptosis via death ligands plays a basic role for lymphocyte homeostasis and lymphoma development. In this study, cutaneous T-cell lymphoma (CTCL) cell lines revealed pronounced resistance to death ligands as compared to cell lines of T-cell acute lymphoblastic leukemia (T-ALL). The proapoptotic activity of tumor necrosis factor (TNF)-alpha was blocked, sensitivity to TNF-related apoptosis-inducing ligand was significantly reduced, and 1/4 CTCL cell lines was resistant to CD95 activation. In parallel, there was no activation of effector caspase-3 and initiator caspase-8 in nonresponsive CTCL cells, whereas caspase-10 was cleaved selectively in sensitive CTCL cells. No indication for a responsibility of typical downstream regulators of apoptosis was obtained, but loss of CD95 was found in 1/4, loss of TNF-R1 in 3/4, loss of caspase-10 in 2/4, loss of Bid in 1/4, and overexpression of cellular flice inhibitory protein was found in 4/4 CTCL cell lines. This clearly indicates an inhibition of apoptosis early in the extrinsic cascade, namely at the formation of the death-inducing signaling complex. Parallels with regard to expression of apoptosis regulators were seen in peripheral blood mononuclear cells and biopsies of CTCL patients. This study may indicate defects in apoptosis in CTCL and may help to guide CTCL therapy.
- Subjects :
- Aged
Apoptosis drug effects
BH3 Interacting Domain Death Agonist Protein physiology
CASP8 and FADD-Like Apoptosis Regulating Protein physiology
Caspase 10 physiology
Cell Line, Tumor
Female
Humans
Leukemia-Lymphoma, Adult T-Cell pathology
Leukemia-Lymphoma, Adult T-Cell physiopathology
Lymphoma, T-Cell, Cutaneous physiopathology
Male
Middle Aged
Receptors, Death Domain physiology
Skin Neoplasms physiopathology
TNF-Related Apoptosis-Inducing Ligand antagonists & inhibitors
TNF-Related Apoptosis-Inducing Ligand physiology
Tumor Necrosis Factor-alpha antagonists & inhibitors
Tumor Necrosis Factor-alpha physiology
fas Receptor physiology
Apoptosis physiology
Lymphoma, T-Cell, Cutaneous pathology
Receptors, Death Domain antagonists & inhibitors
Signal Transduction physiology
Skin Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1523-1747
- Volume :
- 127
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of investigative dermatology
- Publication Type :
- Academic Journal
- Accession number :
- 17495957
- Full Text :
- https://doi.org/10.1038/sj.jid.5700868