• Jie Chen, Qimin Zhou, Shuai Li, Rongsong Ling, Yiwei Zhao, Demeng Chen, Anxun Wang, and Yang Cao.
• Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China.
• Transl Res. 2024 Jun 1; 268: 283928-39.

AbstractTyrosine 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 anlotinib-resistant 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.Copyright © 2024. Published by Elsevier Inc.

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