Hellin A C, Calmant P, Gielen J, Bours V, Merville M P
Laboratory of Medical Chemistry, University of Liège, Belgium.
Oncogene. 1998 Mar 5;16(9):1187-95. doi: 10.1038/sj.onc.1201638.
Anthracycline drugs are widely used for the treatment of solid tumors and leukemia, but the molecular basis of their biological effect is still poorly understood. In the HCT116 colon carcinoma cell line, which retains a wild-type inducible p53 gene, we show that the anthracycline daunomycin is a potent inducer of p53 and NF-kappaB transcription factors. Nuclear accumulation of p53 protein occurred because of increased protein stability and enhanced gene expression. In addition, daunomycin induced the p53 promoter through the binding of p50/p65 NF-kappaB heterodimers to the kappaB site in the p53 promoter. Under our conditions, the free radical scavengers NAC and PDTC were not able to block NF-kappaB activation or p53 induction, indicating that reactive oxygen intermediates were not involved in the cellular response to daunomycin stimulation. Overexpression of a stable unresponsive IkappaBalpha mutant in HCT116 cells resulted in a complete inhibition of the NF-kappaB activation but only a partial impairment of the p53 protein accumulation induced by daunomycin. We conclude that the p53-activating signal generated by daunomycin is partially regulated by NF-kappaB.
蒽环类药物广泛用于实体瘤和白血病的治疗，但其生物学效应的分子基础仍知之甚少。在保留野生型可诱导p53基因的HCT116结肠癌细胞系中，我们发现蒽环类药物柔红霉素是p53和核因子-κB（NF-κB）转录因子的有效诱导剂。p53蛋白的核内积聚是由于蛋白质稳定性增加和基因表达增强所致。此外，柔红霉素通过p50/p65 NF-κB异二聚体与p53启动子中的κB位点结合来诱导p53启动子。在我们的实验条件下，自由基清除剂N-乙酰半胱氨酸（NAC）和吡咯烷二硫代氨基甲酸盐（PDTC）无法阻断NF-κB的激活或p53的诱导，这表明活性氧中间体不参与细胞对柔红霉素刺激的反应。在HCT116细胞中过表达稳定的无反应性IκBα突变体导致NF-κB激活完全被抑制，但柔红霉素诱导的p53蛋白积累仅部分受损。我们得出结论，柔红霉素产生的p53激活信号部分受NF-κB调控。
