The STAT3/NFIL3 signaling axis-mediated chemotherapy resistance is reversed by Raddeanin A via inducing apoptosis in choriocarcinoma cells.

Abstract

Chemotherapy resistance is the major issue of choriocarcinoma. Apoptosis always is the ultimate outcome of chemotherapeutic drugs, which considered one of the reasons of resistance. We investigated the role of STAT3/NFIL3 signaling‐inhibited apoptosis in chemotherapy resistance and whether Raddeanin A (RA) could be a new drug to reverse resistance. Established three drug‐resistant cell lines as JEG‐3/MTX, JEG‐3/5‐FU, and JEG‐3/VP16. NFIL3 and STAT3 expression was evaluated in the cells. The IC50 value, apoptosis rate and apoptins were observed with transfection of siNFIL3, Lenti‐OE™‐NFIL3, shSTAT3, and Lenti‐OE™‐STAT3 or RA treatment. In addition, the luciferase reporter analysis and co‐immunoprecipitation assays were used to investigate the relation of STAT3 and NFIL3. Hyper‐activation of STAT3 and NFIL3 expression were observed in three drug‐resistant cell lines. STAT3 enhanced NFIL3 transcriptional activity by binding the relative promoter region. Activated STAT3/NFIL3 pathway caused low rate of apoptosis which resulted in chemotherapy resistance. RA reduced the resistance index of resistant cells and induced caspase 3 dependent apoptosis, meanwhile it repressed the STAT3/NFIL3 activation. STAT3/NFIL3 axis‐inhibited apoptosis is a novel mechanism of chemotherapy resistance in choriocarcinoma. With the suppression of STAT3/NFIL3 axis and apoptosis induction, RA is a potential agent or lead candidate for improving chemotherapy.