MEF2A restrains cisplatin resistance in gastric cancer cells by modulating NFKBIA/NF-κB signaling pathway.

Abstract

Cisplatin (DDP) resistance represents a pivotal contributing factor to chemotherapy failure and adverse patient outcomes in gastric cancer (GC). The objective of the present study was to investigate the roles and underlying mechanisms of myocyte enhancer factor 2A (MEF2A) in DDP resistance in GC. GC cell line AGS and MKN-45 cells were applied to construct DDP-resistant cells. CCK-8, colony formation, and flow cytometry methods were validated for determining the IC50 value of DDP and cell survival of GC cells. qRT-PCR and western blotting analysis quantified the molecular levels at mRNA and protein, respectively. Chromatin immunoprecipitation and dual-luciferase assays validated the molecular relationship between MEF2A and NF-κB inhibitor alpha (NFKBIA). Roles of MEF2A in in vivo were performed employing a xenograft model. The results showed that NFKBIA was greatly decreased in DDP-resistant AGS and MKN-45 cells compared to their respective parental cells. Increasing NFKBIA expression impaired the IC50 value of DDP and cell survival in DDP-resistant cells, while these alterations were rescued upon TNF-α treatment. Mechanistically, MEF2A acts as a transcriptional activator of NFKBIA, which led to the reduction of phosphorylation of p65 and cytoplasmic retention. Moreover, MEF2A overexpression promoted the sensitivity of GC cells to DDP and tumor growth, whereas these effects were partially reversed by NFKBIA silence. Collectively, MEF2A mitigated the DDP resistance in GC cells by modulatory actions on the NFKBIA/NF-κB signaling, shedding light on MEF2A/NFKBIA might be a promising intervention target for improving DDP resistance in GC.