METTL3 promotes chemoresistance in small cell lung cancer by inducing mitophagy

Abstract

Background Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. Although most patients are initially sensitive to first-line combination chemotherapy with cisplatin and etoposide, chemotherapy drug resistance easily develops and quickly leads to tumour progression. Therefore, understanding the mechanisms of chemotherapy drug resistance and how to reverse it is key to improving the prognosis of patients with SCLC. Moreover, N6-methyladenosine (m6A) is the most abundant mRNA modification and is catalysed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. Methods The effects of METTL3 on chemoresistance in SCLC cells were determined using qRT–PCR, Western blotting, immunohistochemistry, cell counting kit (CCK-8) assays, flow cytometry, and tumorigenicity experiments. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP qPCR, immunofluorescence, and drug inhibitor experiments were performed to confirm the molecular mechanism of Decapping Protein 2 (DCP2), which is involved in the chemoresistance of SCLC. Results In the present study, we found that METTL3 is a marker for poor SCLC prognosis, and it is highly expressed in chemoresistant SCLC cells. METTL3 promotes SCLC chemoresistance by positively regulating mitophagy. METTL3 induces m6A methylation of DCP2 and causes the degradation of DCP2, which promotes mitochondrial autophagy through the Pink1-Parkin pathway, leading to chemotherapy resistance. We also found that STM2457, a novel METTL3 inhibitor, can reverse SCLC chemoresistance. Conclusions The m6A methyltransferase METTL3 regulates Pink1-Parkin pathway-mediated mitophagy and mitochondrial damage in SCLC cells by targeting DCP2, thereby promoting chemotherapy resistance in patients with SCLC.

The METTL3/TRAP1 Axis as a Key Regulator of 5-Fluorouracil Chemosensitivity in Colorectal Cancer

“…Emerging evidence links METTL3 to drug resistance in various cancer cells. For instance, it governs resistance to cisplatin in lung cancer by inducing mitophagy [25]. Moreover, METTL3 has implications in drug resistance within pancreatic cancer [27].…”

Targeting RNA modifications with pharmacological agents: New frontiers in cancer therapy

“…METTL3 mediates resistance to other chemotherapeutic drugs, including platinum-etoposide in Small Cell Lung Cancer (SCLC), doxorubicin, 5-fluorouracil (5-FU), and oxaliplatin in CRC, Idarubicin in AML, and docetaxel in breast cancer. 114,[118][119][120][121][122] Downregulation of METTL3 also associates with resistance to daunorubicin and cytarabine in AML. 114 The m6A erasers FTO and ALKBH5 also mediate chemoresistance in cancer.…”

“…The result is replicable in in vivo model, expanding the lifespan of mice with minimal toxicity observed 153 . In addition to the oncogenic role, METTL3 is responsible for SCLC chemoresistance and STM2457 successfully reversed the chemoresistant in vitro and in vivo 121 …”

“…SCLC (METTL3 induce chemoresistance to the platinumetoposide therapy) [121] Synergise with anti-PD-1 HCC [140] STM3006 Induce interferon responses and enhance cytotoxic CD8+ T cells response.…”

“…153 In addition to the oncogenic role, METTL3 is responsible for SCLC chemoresistance and STM2457 successfully reversed the chemoresistant in vitro and in vivo. 121 Very recently, the competitive inhibitor STM3006 was published. 142 It has 20-fold increased cellular potency compared with STM2457 and potently inhibits proliferation but induces apoptosis of multiple cell lines.…”