METTL3 promotes chemoresistance in small cell lung cancer by inducing mitophagy
Background: Small cell lung cancer (SCLC) is the most aggressive form of lung cancer. While many patients initially respond to first-line chemotherapy with cisplatin and etoposide, resistance to these drugs often develops quickly, leading to tumor progression. Understanding the mechanisms behind chemotherapy resistance and finding ways to overcome it is crucial for improving patient outcomes in SCLC. N6-methyladenosine (m6A) is the most common modification of mRNA and is catalyzed by the methyltransferase complex, with methyltransferase-like 3 (METTL3) being the sole catalytic subunit.
Methods: To investigate the role of METTL3 in chemoresistance in SCLC cells, we used a variety of techniques, including qRT-PCR, Western blotting, immunohistochemistry, CCK-8 assays, flow cytometry, and tumorigenicity experiments. We also employed methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP qPCR, immunofluorescence, and drug inhibitor experiments to explore the molecular mechanism by which Decapping Protein 2 (DCP2) contributes to chemoresistance in SCLC.
Results: Our study revealed that METTL3 is a marker of poor prognosis in SCLC and is highly expressed in chemoresistant SCLC cells. METTL3 promotes chemoresistance by enhancing mitophagy. Specifically, METTL3 induces m6A methylation of DCP2, leading to its degradation and subsequent promotion of mitochondrial autophagy through the Pink1-Parkin pathway, which drives chemotherapy resistance. Additionally, we found that STM2457, a novel METTL3 inhibitor, can reverse this chemoresistance in SCLC cells.
Conclusions: METTL3, through its regulation of the Pink1-Parkin pathway-mediated mitophagy, contributes to chemotherapy resistance in SCLC by targeting DCP2. This insight opens potential therapeutic avenues for overcoming chemoresistance in SCLC patients.