IKK2的药理学抑制剂AS602868揭示了肿瘤坏死因子-α在Jurkat白血病细胞中的凋亡潜力。

AS602868, a pharmacological inhibitor of IKK2, reveals the apoptotic potential of TNF-alpha in Jurkat leukemic cells.

作者信息

Frelin Catherine, Imbert Véronique, Griessinger Emmanuel, Loubat Agnès, Dreano Michel, Peyron Jean-François

机构信息

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.

出版信息

Oncogene. 2003 Nov 6;22(50):8187-94. doi: 10.1038/sj.onc.1206963.

DOI:10.1038/sj.onc.1206963

PMID:14603259

Abstract

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.

摘要

核因子κB转录因子通过诱导抗凋亡基因，促进多种细胞类型的存活。用AS602868（一种与ATP结合竞争的特异性抑制剂）对IKK2激酶进行药理阻断，可防止肿瘤坏死因子-α（TNF-α）诱导的Jurkat白血病T细胞中的核因子κB激活。虽然TNF-α本身对Jurkat细胞的存活没有影响，但添加AS602868会诱导细胞死亡，通过DNA片段化和亚G1期分析可见。在用TNF-α+AS602868联合处理的细胞中，观察到线粒体膜电位破坏，随后半胱天冬酶9和3被激活。定量实时PCR表明，AS602868可阻止TNF-α诱导编码细胞凋亡抑制蛋白2（c-IAP-2）、Bcl-x、Bfl-1/A1和肿瘤坏死因子受体相关因子1（Traf-1）的抗凋亡基因。因此，使用特异性IKK2抑制剂似乎是一种增加细胞对凋亡效应物敏感性的有趣药物策略。