Back to Search
Start Over
GD3, an overexpressed tumor-derived ganglioside, mediates the apoptosis of activated but not resting T cells.
- Source :
-
Cancer research [Cancer Res] 2009 Apr 01; Vol. 69 (7), pp. 3095-104. Date of Electronic Publication: 2009 Mar 10. - Publication Year :
- 2009
-
Abstract
- We previously elucidated an important role for gangliosides in renal cell carcinoma-mediated T lymphocyte apoptosis, although the mechanism by which they mediated lymphocyte death remained unclear. Here, we show that when added in purified form, GD3 is internalized by activated T cells, initiating a series of proapoptotic events, including the induction of reactive oxygen species (ROS), an enhancement of p53 and Bax accumulation, an increase in mitochondrial permeability, cytochrome c release, and the activation of caspase-9. GD3-induced apoptosis of activated T cells was dose dependent and inhibitable by pretreating the lymphocytes with N-acetylcysteine, cyclosporin A, or bongkrekic acid, emphasizing the essential role of ROS and mitochondrial permeability to the process. Ganglioside-induced T-cell killing was associated with the caspase-dependent degradation of nuclear factor-kappaB-inducible, antiapoptotic proteins, including RelA; this suggests that their loss is initiated only after the cascade is activated and that their disappearance amplifies but not triggers GD3 susceptibility. Resting T cells did not internalize appreciable levels of GD3 and did not undergo any of the proapoptotic changes that characterize activated T lymphocytes exposed to the ganglioside. RelA overexpression endows Jurkat cells with resistance to GD3-mediated apoptosis, verifying the role of the intact transcription factor in mediating protection from the ganglioside.
- Subjects :
- Acetylcysteine pharmacology
Antioxidants pharmacology
Apoptosis drug effects
Carcinoma, Renal Cell immunology
Carcinoma, Renal Cell pathology
Caspase 8 metabolism
Caspase 9 metabolism
Caspase Inhibitors
Cell Line, Tumor
Cell Membrane Permeability
Cytochromes c immunology
Cytochromes c metabolism
Gangliosides pharmacokinetics
Glioblastoma immunology
Glioblastoma pathology
Humans
Jurkat Cells
Kidney Neoplasms immunology
Kidney Neoplasms pathology
Lymphocyte Activation
Mitochondrial Membranes metabolism
Reactive Oxygen Species metabolism
T-Lymphocytes cytology
T-Lymphocytes drug effects
T-Lymphocytes metabolism
Apoptosis immunology
Gangliosides immunology
T-Lymphocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 69
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 19276353
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-08-3776