Alpha-tocopheryl succinate sensitises a T lymphoma cell line to TRAIL-induced apoptosis by suppressing NF-kappaB activation.
Activation of nuclear factor-kappaB (NF-kappaB) can interfere with induction of apoptosis triggered by the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL; Apo2L). Therefore, agents that suppress NF-kappaB activation may sensitise cells to TRAIL-dependent apoptosis. Exposure of Jurkat cells to TRAIL resulted in massive and saturable apoptosis induction, following an initial lag time. This lag was abolished by pretreatment of the cells with subapoptotic doses of alpha-tocopheryl succinate (alpha-TOS) or the proteasome inhibitor MG132. Exposure of the cells to TRAIL led to a rapid, transient activation of NF-kappaB, a process that was suppressed by cell pretreatment with alpha-TOS or MG132. Activation of NF-kappaB by TNF-alpha prior to TRAIL exposure increased resistance of the cells to TRAIL-mediated apoptosis. We conclude that alpha-TOS sensitises cells to TRAIL killing, at least in some cases, through inhibition of NF-kappaB activation. This further supports the possibility that this semisynthetic analogue of vitamin E is a potential adjuvant in cancer treatment, such as in the case of TRAIL-mediated inhibition of cancer.
Dalen
H
H
Department of Pathology, The Gade Institute, University of Bergen, Norway.
Neuzil
J
J
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D004347:Drug Interactions; D006801:Humans; D019169:Jurkat Cells; D008223:Lymphoma; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013601:T-Lymphocytes / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D024505:Tocopherols; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D014810:Vitamin E; D024505:Tocopherols