Abstract
NF-κB 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-α-induced NF-κB activation in Jurkat leukemic T cells. While TNF-α 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-α+AS602868. Quantitative real-time PCR demonstrated that AS602868 prevented TNF-α 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.
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Acknowledgements
We would like to thank Drs Ched Grimshaw and Shripad Bhagwat (Celgene Corporation, USA) for sharing information about properties of AS602868. This work was supported by institutional grants from INSERM, by a grant from La Fondation de France, comité Leucémies and by a research grant from Serono International SA (Geneva, Switzerland).
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Frelin, C., Imbert, V., Griessinger, E. et al. AS602868, a pharmacological inhibitor of IKK2, reveals the apoptotic potential of TNF-α in Jurkat leukemic cells. Oncogene 22, 8187–8194 (2003). https://doi.org/10.1038/sj.onc.1206963
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DOI: https://doi.org/10.1038/sj.onc.1206963
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