RARB Enhances the Sensitivity of Cisplatin-Resistant Non-Small Cell Lung Cancer Cells by Downregulating NCOA3

Abstract

Background: Drug resistance in non-small cell lung cancer (NSCLC) cells will affect the therapeutic efficacy of cisplatin (DDP) in treatment. Retinoic acid receptor beta (RARB) has been implicated in the prognosis of NSCLC. This study aimed to investigate the mechanism of RARB in the drug resistance of NSCLC cells. Methods: Differential gene expression in drug-resistant NSCLC cells was analyzed using bioinformatics. DDP-resistant NSCLC cells were generated through continuous exposure to DDP over six months. mRNA and protein levels of RARB, nuclear receptor coactivator 3 (NCOA3), and phosphorylated p65 (p-p65) were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Cell viability was assessed using the cell counting kit-8 (CCK-8) assay, and the half-maximal inhibitory concentration (IC₅₀) of DDP was determined. Cell apoptosis was analyzed via flow cytometry. A rescue experiment was conducted to explore whether the regulatory effect of RARB on DDP-resistant NSCLC cell sensitivity was mediated by NCOA3 regulation. Results: RARB expression was downregulated in DDP-resistant NSCLC cells, while NCOA3 and p-p65 expressions were upregulated. RARB overexpression (RARB-OE) inhibited cell viability and enhanced the sensitivity and apoptosis of DDP-resistant NSCLC cells, whereas overexpression of NCOA3 (NCOA3-OE) had the opposite effect. Additionally, RARB-OE reduced NCOA3 and p-p65 levels in DDP-resistant NSCLC cells, while NCOA3-OE increased p-p65 levels. Notably, the impact of RARB-OE and NCOA3-OE on DDP-resistant NSCLC cells was reversed following co-transfection. Conclusion: RARB enhances the sensitivity of DDP-resistant NSCLC cells by downregulating NCOA3.