AS602868, a pharmacological inhibitor of IKK2, reveals the apoptotic potential of TNF-alpha in Jurkat leukemic cells.
NF-kappaB transcription factors promote survival in numerous cell types via induction of antiapoptotic genes. Pharmacological blockade of the IKK2 kinase with AS602868, a specific inhibitor that competes with ATP binding, prevented TNF-alpha-induced NF-kappaB activation in Jurkat leukemic T cells. While TNF-alpha by itself had no effect on Jurkat survival, the addition of AS602868 induced cell death, visualized by DNA fragmentation and sub-G1 analysis. A disruption of the mitochondrial potential followed by activation of caspases 9 and 3 was observed in cells treated by the combination TNF-alpha+AS602868. Quantitative real-time PCR demonstrated that AS602868 prevented TNF-alpha induction of the antiapoptotic genes coding for c-IAP-2, Bclx, Bfl-1/A1 and Traf-1. The use of a specific IKK2 inhibitor appears, therefore, as an interesting pharmaceutical strategy to increase the cell's sensitivity towards apoptotic effectors.
Frelin
Catherine
C
INSERM U526, Activation des Cellules Hématopoïétiques, Physiologie de la Survie et de la Mort Cellulaires et Infections Virales, IFR 50 Génétique et Signalisation Moléculaires, Faculté de Médecine Pasteur, 06107 Nice cedex 02, France.
Imbert
Véronique
V
Griessinger
Emmanuel
E
Loubat
Agnès
A
Dreano
Michel
M
Peyron
Jean-François
JF
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000188:drug therapy*; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate