Lactate promoted cisplatin resistance in NSCLC by modulating the m6A modification-mediated FOXO3/MAGI1-IT1/miR-664b-3p/IL-6R axis

• Published in: Neoplasia (New York, N.Y.) Vol. 48; p. 100960
• Main Authors: Bo, Wei, Yu, Ning, Wang, Xiaokai, Wang, Chun, Liu, Chunying
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2024; Neoplasia Press; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing; Adenine - analogs & derivatives; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cell Adhesion Molecules; Cell Line, Tumor; Cell Proliferation; Cisplatin - pharmacology; Cisplatin resistance; Drug Resistance, Neoplasm - genetics; Forkhead Box Protein O3; FOXO3; Guanylate Kinases; Humans; Lactate; Lactic Acid; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; MAGI1-IT1; MicroRNAs - genetics; NSCLC; Original Research; Transcription Factors; ceRNA; MAGI1-IT1; YTHDF2; PCNA; NSCLC; Lactate; IHC; LncRNAs; qRT-PCR; MeRIP-PCR; FOXO3; FOXOs; ChIP; DDP; TUNEL; shRNA; IC50; EdU; RIP; m6A; CCK-8; Cisplatin resistance; IL6R
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2023.100960

Cisplatin resistance is one of the major obstacles in non-small cell lung cancer (NSCLC) treatment. Intriguingly, elevated lactate levels were observed in cisplatin-resistant cells, which spurred further investigation into their underlying biological mechanisms. Lactate levels were measured by lactate detection kit. Cisplatin-resistance NSCLC cells were established using progressive concentration of cisplatin. Cell viability, proliferation, and apoptosis were detected by CCK-8, EdU, and flow cytometry, respectively. Cell proliferation in vivo was determined by immunohistochemistry of Ki67 and apoptotic cells were calculated by the TUNEL. MeRIP-PCR was used to measure FOXO3 m6A levels. The interactions of genes were analyzed via RIP, ChIP, Dual-luciferase reporter, and RNA pull-down, respectively. Elevated lactate levels were observed in both NSCLC patients and cisplatin-resistance cells. Lactate treatment increased cisplatin-resistance cell viability in vitro and promoted tumor growth in vivo. Mechanistically, lactate downregulated FOXO3 by YTHDF2-mediated m6A modification. FOXO3 transcriptionally reduced MAGI1-IT1 expression. FOXO3 overexpression inhibited the lactate-induced promotion of cisplatin resistance in NSCLC, which were reversed by MAGI1-IT1 overexpression. MAGI1-IT1 and IL6R competitively bound miR-664b-3p. FOXO3 overexpression or MAGI1-IT1 knockdown repressed lactate-mediated cisplatin resistance in vivo. Lactate promoted NSCLC cisplatin resistance through regulating FOXO3/MAGI1-IT1/miR-664b-3p/IL6R axis in YTHDF2-mediated m6A modification.