PI-3K/Akt and NF-kappaB/IkappaBalpha pathways are activated in Jurkat T cells in response to TRAIL treatment.
The aim of this work was to evaluate the involvement of survival pathways in the response of Jurkat T leukaemic cells sensitive to the cytotoxic action of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/Apo2L. Jurkat T cells express TRAIL-R2/DR5 and TRAIL-R4/DcR2 receptors and start to die by apoptosis early (3 h) upon TRAIL administration reaching a dose-dependent increase in the percentage of dead cells within 48 h (up to 85-90%). This increase in cell death is accompanied by a dose-dependent significant (P < 0.05) increase in the G0/G1 phase of the cell cycle and reverted by the treatment with a broad inhibitor of caspases, z-VAD-fmk. Co-treatment of the cells with inhibitors of PI-3 kinase (LY294002) and nuclear factor kappa B (NF-kappaB) (SN50) pathways leads to an earlier significantly increased cytotoxicity, respectively in the form of apoptosis and necrosis. Consistently with the data obtained with the pharmacological inhibitors, the activation and nuclear translocation of both PI-3K and NF-kappaB were observed. In summary, our results provide evidence that even in sensitive neoplastic cells TRAIL paradoxically activates pro-survival pathways, which protect against TRAIL-mediated death since their inhibition leads to an earlier and increased cytotoxicity.
Zauli
Giorgio
G
Dipartimento di Morfologia Umana Normale, Università di Trieste, Via Manzoni, Trieste, Italy.
Sancilio
Silvia
S
Cataldi
Amelia
A
Sabatini
Nadia
N
Bosco
Domenico
D
Di Pietro
Roberta
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002470:Cell Survival; D002867:Chromones / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016253:Microscopy, Immunoelectron; D009025:Morpholines / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D009025:Morpholines; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; C000606204:NFKBIA protein, human; C505653:TNFSF10 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human