Circular RNA FOXO3 accelerates glycolysis and improves cisplatin sensitivity in lung cancer cells via the miR‑543/Foxo3 axis

Abstract

Non-small cell lung cancer (NSCLC) is the most common cause of cancer-associated mortality worldwide. Our previous study revealed that circular RNA (circRNA)-FOXO3 is highly expressed in lung cancer and inhibits cell proliferation. However, to the best of our knowledge, at present, no study has focused on the specific mechanism of circRNA-FOXO3 in drug resistance. Therefore, the present study aimed to provide novel perspectives on the role of circRNA-FOXO3 in cisplatin (DDP) resistance in NSCLC. A Cell Counting Kit-8 assay was used to determine the viability of cells overexpressed with circRNA-FOXO3 and under DDP treatment. Glycolysis was analyzed by measuring glucose consumption and lactate production. The interaction of circRNA-FOXO3, microRNA 543 (miR-543) and Foxo3 was confirmed using a dual-luciferase reporter assay. It was revealed that circRNA-FOXO3 improved cell sensitivity to DDP and repressed glycolysis in DDP-sensitive and DDP-resistant NSCLC cells. Bioinformatics analysis, luciferase reporter assays, quantitative PCR and RNA pull-down assays were employed to verify the binding of circRNA-FOXO3 to miR-543. Functionally, inhibition of miR-543 could sensitize NSCLC cells to DDP, and overexpression of miR-543 at least partially abolished the circRNA-FOXO3-induced decrease in chemoresistance. Furthermore, it was revealed that Foxo3 was a direct target of miR-543. Notably, the inhibitory action of miR-543 silencing on DDP resistance and glycolysis was reversed by overexpression of Foxo3 in DDP-sensitive and DDP-resistant NSCLC cells. In conclusion, the present study demonstrated that circRNA-FOXO3 promoted DDP sensitivity in NSCLC cells by regulating the miR-543/Foxo3 axis-mediated glycolysis balance. The present findings may provide novel perspectives for the treatment of patients with NSCLC resistant to DDP.