LRPPRC contributes to the cisplatin resistance of lung cancer cells by regulating MDR1 expression

Abstract

The development of multidrug resistance is the major obstacle to successful lung cancer chemotherapy. Cancer cells gain resistance through increased levels of P-glycoprotein (P-gp), which is encoded by the multidrug resistance-associated protein 1 (MDR1) gene. Leucine-rich PPR motif-containing protein (LRPPRC), a member of the PPR family, has been verified to regulate the transcription of MDR1. This regulation is influenced by the methylation status of the GC -100 box in the MDR1 promoter. The present study aimed to investigate the effect of LRPPRC on cisplatin (DDP) resistance in lung cancer cells and explore the underlying mechanism. DDP-resistant non-small cell lung cancer cell lines (A549/DDP, H1299/DDP) were generated. The expression levels of LRPPRC and P-gp/MDR1, investigated by qPCR and western blot analysis, were increased in the A549/DDP and H1299/DDP cells compared with that in the parental cells. LRPPRC silencing with shRNA increased DDP sensitivity in vitro and in vivo. LRPPRC silencing inhibited the level of LRPPRC binding with the MDR1 promoter, investigated by chromatin immunoprecipitation-qPCR, and the corresponding MDR1 expression. Demethylation treatment rescued the decrease in the level of LRPPRC binding with MDR1 and the corresponding expression of MDR1 and the increase in DDP sensitivity due to LRPPRC silencing. Our study suggests that LRPPRC contributes to DDP resistance in lung cancer cells by regulating MDR1 transcription. Thus, LRPPRC may serve as a potential molecular target for chemo-resistance reversal in lung cancer.