Increased and correlated nuclear factor-kappa B and Ku autoantigen activities are associated with development of multidrug resistance.

Abstract

In this study, we investigated possible engagement of NF-kappaB and Ku autoantigen (Ku) activation in development of multidrug resistance (MDR) and circumvention of MDR by modulation of NF-kappaB and Ku. The NF-kappaB activity and NF-kappaB p65 subunit level were constitutively higher in MDR cells than in drug-sensitive parental cells. Interestingly, a faster running NF-kappaB DNA binding complex was identified as Ku, a DNA damage sensor and a key double strand break repair protein, and was positively correlated with the NF-kappaB activity in MDR cells and Ku- or both subunits of NF-kappaB-transfected cells. Also both NF-kappaB 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-kappaB and Ku in MDR cells and subsequently potentiated the cytotoxic activity of anticancer drugs. Our results proposed that the NF-kappaB and Ku activation could be one of multi-factorial MDR mechanism, and PKA inhibitor, likely via inhibition of NF-kappaB and Ku activities, could enhance the effectiveness of anticancer drugs against MDR cells with high activities of NF-kappaB and Ku.