Retinoid-induced activation of NF-κB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells

被引:19
作者
Mathieu, J
Giraudier, S
Lanotte, M
Besançon, F
机构
[1] Hop St Louis, INSERM, U685, Ctr Hayem, F-75475 Paris, France
[2] Inst Gustave Roussy, INSERM, U362, F-94805 Villejuif, France
关键词
apoptosis; NF-kappa B; ROS; JNK; ATRA; APL;
D O I
10.1038/sj.onc.1208889
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
All-trans retinoic acid (ATRA) significantly improves the survival of patients with acute promyelocytic leukemia (APL) by inducing granulocytic differentiation of leukemia cells. Since an activation of the transcription factor NF-kappa B occurs during ATRA-induced maturation of APL cells, a mechanistic link between these two processes was investigated. Using an in vitro model for APL, we report that ectopic overexpression of a repressor of NF-kappa B activation did not affect granulocytic differentiation. Importantly, NF-kappa B inhibition markedly resulted in a decreased viability of the differentiated cells, which correlated with increased apoptosis. Apoptosis was accompanied by a sustained activation of the c-Jun N-terminal kinase (JNK). Inhibition of JNK by the specific inhibitor SP600125 or by transfection of a dominant-negative mutant of JNK1 reduced the percentage of apoptotic cells, thus showing that JNK activation constitutes a death signal. Furthermore, impairment of NF-kappa B activation resulted in increased levels of reactive oxygen species (ROS) upon ATRA treatment. ROS accumulation was suppressed by the antioxidant butylated hydroxyanisol, which also abolished ATRA-induced JNK activation and apoptosis. Altogether, our results demonstrate an antiapoptotic effect of NF-kappa B activation during ATRA-induced differentiation of NB4 cells and identify repression of ROS-mediated JNK activation as a mechanism for this effect. Our observations also suggest that NF-kappa B signalling may contribute to an accumulation of mature APL cells and participate in the development of ATRA syndrome.
引用
收藏
页码:7145 / 7155
页数:11
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