In this study, we investigated possible engagement of NF-kB and Ku autoantigen (Ku) activation in development of multidrug resistance (MDR) and circumvention of MDR by modulation of NF-kB and Ku. The NF-kB activity and NF-kB p65 subunit level were constitutively higher in MDR cells than in drug-sensitive parental cells. Interestingly, a faster running NF-kB DNA binding complex was identi®ed as Ku, a DNA damage sensor and a key double strand break repair protein, and was positively correlated with the NF-kB activity in MDR cells and Ku-or both subunits of NF-kB-transfected cells. Also both NF-kB and Ku activities were activated or inhibited by treatment with etoposide (VP-16) or MG-132 (a proteasome inhibitor), respectively. Furthermore, PKA inhibitor suppressed markedly the constitutive and drug-induced activities of NF-kB and Ku in MDR cells and subsequently potentiated the cytotoxic activity of anticancer drugs. Our results proposed that the NF-kB and Ku activation could be one of multi-factorial MDR mechanism, and PKA inhibitor, likely via inhibition of NF-kB and Ku activities, could enhance the e ectiveness of anticancer drugs against MDR cells with high activities of NF-kB and Ku. Oncogene (2001) 20, 6048 ± 6056.
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