Increased and correlated nuclear factor-kappa B and Ku autoantigen activities are associated with development of multidrug resistance.
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.
Um
J H
JH
Department of Biochemistry, College of Medicine, Pusan National University, Pusan 602-739, South Korea.
Kang
C D
CD
Lee
B G
BG
Kim
D W
DW
Chung
B S
BS
Kim
S H
SH
D034961:Antigens, Nuclear; D000970:Antineoplastic Agents / Q000494:pharmacology; D002227:Carbazoles; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D000072200:Ku Autoantigen; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D013449:Sulfonamides; D014407:Tumor Cells, Cultured
D034961:Antigens, Nuclear; D000970:Antineoplastic Agents; D002227:Carbazoles; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D007546:Isoquinolines; D016328:NF-kappa B; D009687:Nuclear Proteins; D011758:Pyrroles; D013449:Sulfonamides; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide