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Regulation of the resistance to TRAIL-induced apoptosis in human primary T lymphocytes: role of NF-kappaB inhibition.
- Source :
-
Molecular immunology [Mol Immunol] 2007 Apr; Vol. 44 (10), pp. 2587-97. Date of Electronic Publication: 2007 Jan 25. - Publication Year :
- 2007
-
Abstract
- Several combined strategies have been recently proposed to overcome the resistance to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) showed by some tumor cells, thus improving the use of this death ligand in antitumor therapy. However, the molecular mechanisms of the tumor selective activity of TRAIL are not completely understood and hence the effects of the combined therapy on normal cells are unknown. Here, we have studied the resistance of primary T lymphocytes to TRAIL-mediated apoptosis. No significant differences were found in the expression of proteins involved in TRAIL-mediated apoptosis between resting and activated T cells. The low expression of death receptors TRAIL-R1/-R2 as well as the high levels of the antiapoptotic proteins TRAIL-R4 and cellular Fas-associated death domain-like IL-1beta-converting enzyme-inhibitory protein (c-FLIP) may explain the lack of caspase-8 activation observed upon TRAIL treatment in both cell types. We have also analyzed the effect of different sensitizing agents such as genotoxic drugs, phosphatidylinositol-3 kinase (PI3K) inhibitors, proteasome inhibitors, microtubule depolymerizing agents, histone deacetylase inhibitors (HDACi), and NF-kappaB inhibitors. Although some of them induced T cell death, only NF-kappaB inhibitors sensitized activated T cells to TRAIL-induced apoptosis, maybe through the regulation of the antiapoptotic proteins TRAIL-R4, c-FLIP(S) and members of the inhibitors of apoptosis proteins (IAP) family. These results question the safety of the combined treatments with TRAIL and NF-kappaB inhibitors against tumors.
- Subjects :
- Antineoplastic Agents pharmacology
CASP8 and FADD-Like Apoptosis Regulating Protein metabolism
Down-Regulation
Drug Resistance, Neoplasm genetics
Enzyme Inhibitors pharmacology
Humans
NF-kappa B antagonists & inhibitors
Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism
T-Lymphocytes immunology
Apoptosis genetics
Drug Resistance, Neoplasm physiology
NF-kappa B physiology
T-Lymphocytes drug effects
TNF-Related Apoptosis-Inducing Ligand pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0161-5890
- Volume :
- 44
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular immunology
- Publication Type :
- Academic Journal
- Accession number :
- 17257681
- Full Text :
- https://doi.org/10.1016/j.molimm.2006.12.015