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Metabolic reprogramming driven by METTL1-mediated tRNA m7G modification promotes acquired anlotinib resistance in oral squamous cell carcinoma
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DOI：10.1016/j.trsl.2024.01.009.png)
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Abstract
En 中文
Tyrosine kinase inhibitors (TKIs) are frequently utilized in the management of malignant tumors. Studies have indicated that anlotinib has a significant inhibitory effect on oral squamous cell carcinoma (OSCC). However, the mechanisms underlying the development of resistance with long-term anlotinib treatment remain obscure. Our research found that METTL1 expression was heightened in anlotinib-resistant OSCC cells. We observed that METTL1 played a role in fostering resistance to anlotinib in both transgenic mouse models and in vitro. Mechanistically, the elevated METTL1 levels in anlotinib-resistant OSCC cells contributed to enhanced global mRNA translation and stimulated oxidative phosphorylation (OXPHOS) through m7G tRNA modification. Bioenergetic profiling demonstrated that METTL1 drived a metabolic shift from glycolysis to OXPHOS in anlotinibresistant OSCC cells. Additionally, inhibition of OXPHOS biochemically negated METTL1 ' s impact on anlotinib resistance. Overall, this study underscores the pivotal role of METTL1-mediated m7G tRNA modification in anlotinib resistance and lays the groundwork for novel therapeutic interventions to counteract resistance in OSCC.
Keywords:
METTL1
tRNA m7G modifications
Mitochondrial metabolic reprogramming
Tumor TKI resistance
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