Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China.
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Transl Res. 2024 Jun;268:28-39. doi: 10.1016/j.trsl.2024.01.009. Epub 2024 Jan 26.
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 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.
酪氨酸激酶抑制剂 (TKIs) 常用于恶性肿瘤的治疗。研究表明，安罗替尼对口腔鳞状细胞癌 (OSCC) 具有显著的抑制作用。然而，长期使用安罗替尼治疗时产生耐药性的机制仍不清楚。我们的研究发现，METTL1 在耐安罗替尼的 OSCC 细胞中表达上调。我们观察到 METTL1 在转基因小鼠模型和体外均在促进耐安罗替尼方面发挥作用。从机制上讲，耐安罗替尼的 OSCC 细胞中升高的 METTL1 水平通过 m7G tRNA 修饰促进了全局 mRNA 翻译并刺激了氧化磷酸化 (OXPHOS)。生物能量分析表明，METTL1 在耐安罗替尼的 OSCC 细胞中驱动了从糖酵解到 OXPHOS 的代谢转变。此外，OXPHOS 的抑制在生化上否定了 METTL1 对安罗替尼耐药性的影响。总的来说，这项研究强调了 METTL1 介导的 m7G tRNA 修饰在安罗替尼耐药性中的关键作用，并为针对 OSCC 耐药性的新型治疗干预措施奠定了基础。
