Anesthetic propofol enhances cisplatin-sensitivity of non-small cell lung cancer cells through N6-methyladenosine-dependently regulating the miR-486-5p/RAP1-NF-κB axis

Abstract

Background Drug resistance is a considerable challenge for chemotherapy in non-small cell lung cancer (NSCLC). Propofol, a commonly used intravenous anesthetics, has been reported to suppress the malignancy of various cancers. However, the effects of propofol on cisplatin (DDP) sensitivity in NSCLC and its molecular mechanisms have not been clearly clarified yet, and the present study aimed to resolve this problem. Methods NSCLC cells were co-treated with propofol and DDP, Cell Counting kit-8 assay, colony formation assay and flow cytometry were conducted to test the role of propofol in regulating DDP-resistance in NSCLC. Next, through conducting quantitative real-time polymerase chain reaction, dual-luciferase gene reporter system and western blot, the responsible molecular axis in propofol regulating the DDP sensitivity in NSCLC was uncovered, and the function verification experiments were performed by transfection with the inhibitors or small interfering RNAs of those molecules. Results Propofol suppressed cell viability, colony formation ability, tumorigenesis, and promoted cell apoptosis to enhance DDP-sensitivity in NSCLC in vitro and in vivo. Propofol increased miR-486-5p level in NSCLC cells and xenograft tumors tissues in a N6-methyladenosine (m6A)-dependent manner, thus inactivating the Ras-associated protein1 (RAP1)-NF-kappaB (NF-κB) axis. Propofol regulated the miR-486-5p/RAP1-NF-κB axis to improve DDP-sensitivity in NSCLC. Conclusions Taken together, this study firstly investigates the detailed molecular mechanisms by which propofol enhanced DDP-sensitivity in NSCLC cells, and a novel m6A-dependent miR-486-5p/RAP1-NF-κB axis is identified to be closely associated with the process.

The Molecular Pathogenesis of Tumor-Suppressive miR-486-5p and miR-486-3p Target Genes: GINS4 Facilitates Aggressiveness in Lung Adenocarcinoma

“…Moreover, the overexpression of miR-486-5p attenuated tumor growth and inhibited metastasis according to in vivo assays [36,37]. A recent study showed that the anesthetic propofol induced the expression of miR-486-5p, resulting in the inhibition of the Ras-associated protein1-NF-κB pathway [38]. These events contributed to cisplatinsensitivity in NSCLC cells [38].…”

Emerging roles of m6A RNA modification in cancer therapeutic resistance

“…Represented by the most learned METTL3, it was revealed that METTL3 promoted resistance to cisplatin by stimulating AKT1 in NSCLC [ 35 ]. However, Ling et al found that METTL3 participated in the re-sensitization to cisplatin mediated by propofol [ 36 ].…”

“…However, Ling et al found that propofol enhanced cisplatin sensitivity dose-dependently via promoting METTL3-mediated m6A methylation. Propofol augments m6A enrichment on pri-miR-486-5p to promote its maturation and further inactivates the Ras-associated protein1 (RAP1)-NF-kappaB (NF-κB) axis, and knockdown of METTL3 reversed the promoting effect [ 36 ]. Besides, METTL3 was negatively regulated by miR-4443, which is enriched in exosomes of cisplatin-resistant NSCLC.…”

Inducing ferroptosis by traditional medicines: a novel approach to reverse chemoresistance in lung cancer

“…Recent studies have shown that propofol, an intravenous anesthetic agent traditionally and widely used for sedation and general anesthesia, exhibits anti-tumor activity against cancer progression in vitro and in vivo (Wang et al, 2018;Gu et al, 2022). Propofol can boost the anti-tumor activity of cisplatin in lung cancer (Huang et al, 2020;Ling et al, 2022;Quan et al, 2022). Mechanistically, propofol decreases cisplatin resistance in NSCLC by inducing ferroptosis, accomplished by upregulating the miR-744-5p/miR-615-3p axis and inhibiting GPX4 .…”