NUCLEAR FACTOR - KAPPA-B-DEPENDENT REGULATION OF P53 GENE-EXPRESSION INDUCED BY DAUNOMYCIN GENOTOXIC DRUG

Anthracycline drugs are widely used for the treatment of solid tumors and leukemia, but the molecular basis of their biological effect is st ill poorly understood, In the HCT 116 colon carcinoma cell line, which retains a wild-type inducible p53 gene, we show that the anthracyclin e daunomycin is a potent inducer of p53 and NF-kappa B transcription f actors, Nuclear accumulation of p53 protein occurred because of increa sed protein stability and enhanced gene expression, In addition, dauno mycin induced the p53 promoter through the binding of p50/p65 NF-kappa B heterodimers to the kappa B site in the p53 promoter, Under our con ditions, the free radical scavengers NAC and PDTC were not able to blo ck NF-kappa B activation or p53 induction, indicating that reactive ox ygen intermediates were not involved in the cellular response to dauno mycin stimulation. Overexpression of a stable unresponsive I kappa B a lpha mutant in HCT116 cells resulted in a complete inhibition of the N F-kappa B activation but only a partial impairment of the p53 protein accumulation induced by daunomycin, We conclude that the p53-activatin g signal generated by daunomycin is partially regulated by NF-kappa B.