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Transcription Factor c-Jun Activation Represses mdr-1 Gene Expression¹

Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China

Expression of mdr-1 is complex and highly regulated. Several lines of evidence indirectly suggest that transcription factor c-Jun may negatively regulate human mdr-1 gene expression. We recently found that salvicine, a novel topoisomerase II inhibitor, is cytotoxic for multidrug resistance (MDR) tumor cells and down-regulates mdr-1 expression in MDR K562/A02 cells. Salvicine also stimulates a significant increase in the level of c-jun mRNA in HL60 cells. This study investigated the relationship between c-Jun activation and down-regulation of mdr-1 expression by salvicine in K562/A02 cells. Reverse-transcription PCR and Western blotting analyses revealed that salvicine suppressed mdr-1 expression in MDR cells and promoted c-jun expression in both MDR and parental K562 cells. Moreover, levels of c-jun expression were enhanced by salvicine before reduction of mdr-1 expression in K562/A02 cells. Furthermore, c-jun antisense oligodeoxynucleotides prevented salvicine-stimulated enhancement of c-Jun protein and reduction of mdr-1 gene expression, but did not affect the increase in c-jun mRNA levels. Salvicine promoted phosphorylation of c-Jun-N-terminal kinase and c-Jun protein in MDR K562/A02 and parental K562 cells. Electrophoretic mobility shift assay analysis showed that salvicine enhanced DNA binding activity of transcription factor activator protein 1. Additionally, c-jun antisense oligodeoxynucleotides also inhibited salvicine-induced apoptosis and cytotoxicity in MDR and parental K562 cells. A possible pathway emerges from these results: salvicine stimulates c-Jun-N-terminal kinase phosphorylation and activation, resulting in c-Jun phosphorylation and activation. Activated c-Jun promotes expression of c-jun itself, represses mdr-1 transcription, and triggers pro-apoptotic signals, resulting in low mdr-1 expression and cell death. The present results demonstrate that transcription factor c-Jun plays a principal role in down-regulation of mdr-1 expression and induction of apoptosis in salvicine-treated human MDR K562/A02 cells, providing new insights into the complicated mechanisms regulating mdr-1 expression. The findings also suggest that c-Jun might be a potential drug target for circumventing tumor MDR.

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