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Drug resistance greatly limits docetaxel efficiency in the treatment of non-small cell lung cancer (NSCLC).Dickkopf 4 (DKK4),a negative regulator of Wnt/β-catenin pathway,is believed to be involved in various human cancers;whereas the association of DKK4 with acquired docetaxel resistance in NSCLC remains unclear.In the present study,we investigated the involvement of DKK4 in the docetaxel-resistant human lung adenocarcinoma A549 (A549/DTX) cells.Our results showed that DKK4 expression was significantly increased in the A549/DTX cells compared with in the A549 cells,as well as in the culture supeatant of A549/DTX cells.DKK4 overexpression increased the resistance of A549 cells to docetaxel.DKK4-knockdown promoted inhibition of A549/DTX cell growth,and reduced the colony formation and invasion capacity of A549/DTX cells.Moreover,DKK4-knockdown promoted the pro-apoptotic effect of docetaxel characterized with caspase 3 activation and inhibition of BCL-2 expression in A549/DTX cells,which was possibly mediated by inducing the activation of c-Jun N-terminal kinase (JNK)-related signaling pathway.Thus,our results indicated that DKK4-knockdown promoted the cytotoxic and pro-apoptotic activity of A549/DTX cells,which suggests a critical role of DKK4 in docetaxel resistance of the A549 cells and provides the potential to combine docetaxel therapy with DKK4 depletion in treating NSCLC.