NDRG1 Downregulates ATF3 and Inhibits Cisplatin-Induced Cytotoxicity in Lung Cancer A549 Cells.

N-myc downstream regulated gene 1 (NDRG1) plays a variety of roles in human cancers. Our previous studies showed that NDRG1 expression is elevated in non-small cell lung cancer and contributes to cancer growth. However, its function in apoptosis and chemoresistance in malignant tumors, including lung cancer, is not yet fully understood. In this study, we investigated the roles of NDRG1 in chemoresistance to cisplatin in lung cancer cells. We found that overexpression of NDRG1 significantly reduced cisplatin-induced cytotoxicity in lung cancer A549 cells, while overexpression of activating transcription factor 3 (ATF3), a stress-inducible gene found to be associated with apoptosis in some human cancers, significantly promoted cytotoxicity ( P < 0.05). Further investigation showed that overexpression of NDRG1 significantly downregulated ATF3 and P53 expression in A549 cells, while overexpression of ATF3 significantly upregulated P53 expression ( P < 0.05). In addition, cisplatin significantly upregulated ATF3, phospho-P53(ser46), and cleaved caspase 3 expression in lung cancer cells, but overexpression of NDRG1 in the presence of cisplatin reduced the level of these proteins elevated by cisplatin ( P < 0.05). While, overexpression of ATF3 significantly promoted the cytoxicity induced by cisplatin in 1299 cells (p<0.05) (Figure 4), but overexpression of NDRG1 didn't regulate the cytoxicity induced by cisplatin (p>0.05). These results indicate that NDRG1 may contribute to cisplatin-resistance in lung cancer, possibly due to its function in the regulation of ATF3 expression.