文章：

范可尼贫血通路抑制头颈癌细胞中的mTOR信号传导并阻止翻译加速

The Fanconi Anemia Pathway Inhibits mTOR Signaling and Prevents Accelerated Translation in Head and Neck Cancer Cells

原文发布日期：6 August 2025

DOI: 10.3390/cancers17152583

类型: Article

开放获取: 是

英文摘要：

Background/Objectives:The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand crosslinks and maintenance of genomic stability. Germline loss of FA pathway function in the inherited Fanconi anemia syndrome leads to increased DNA damage and a range of clinical phenotypes, including a heightened risk of head and neck squamous cell carcinoma (HNSCC). Non-synonymous FA gene mutations are also observed in up to 20% of sporadic HNSCCs. The mechanistic target of rapamycin (mTOR) is known to stimulate cell growth, anabolic metabolism including protein synthesis, and survival following genotoxic stress.Methods/Results:Here, we demonstrate that FA− deficient (FA−) HNSCC cells exhibit elevated intracellular amino acid levels, increased total protein content, and an increase in protein synthesis indicative of enhanced translation. These changes are accompanied by hyperactivation of the mTOR effectors translation initiation factor 4E Binding Protein 1 (4E-BP1) and ribosomal protein S6. Treatment with the mTOR inhibitor rapamycin reduced the phosphorylation of these targets and blocked translation specifically in FA− cells but not in their isogenic FA− proficient (FA+) counterparts. Rapamycin-mediated mTOR inhibition sensitized FA− but not FA+ cells to rapamycin under nutrient stress, supporting a therapeutic metabolism-based vulnerability in FA− cancer cells.Conclusions:These findings uncover a novel role for the FA pathway in suppressing mTOR signaling and identify mTOR inhibition as a potential strategy for targeting FA− HNSCCs.

摘要翻译： 

背景/目的：范可尼贫血（FA）通路对于DNA链间交联修复和基因组稳定性维持至关重要。遗传性范可尼贫血综合征中FA通路功能的种系缺失会导致DNA损伤增加及一系列临床表型，包括头颈部鳞状细胞癌（HNSCC）发病风险升高。在高达20%的散发性HNSCC中也观察到FA基因的非同义突变。已知雷帕霉素机制靶蛋白（mTOR）能够刺激细胞生长、促进包括蛋白质合成在内的合成代谢，并在基因毒性应激后维持细胞存活。 方法/结果：本研究发现FA缺陷型（FA−）HNSCC细胞表现出细胞内氨基酸水平升高、总蛋白含量增加以及蛋白质合成增强所提示的翻译过程活跃。这些变化伴随着mTOR效应分子翻译起始因子4E结合蛋白1（4E-BP1）和核糖体蛋白S6的过度激活。使用mTOR抑制剂雷帕霉素处理可降低这些靶点的磷酸化水平，并特异性抑制FA−细胞的翻译过程，而对同基因型FA功能正常（FA+）细胞无此效应。在营养应激条件下，雷帕霉素介导的mTOR抑制能增强FA−细胞（而非FA+细胞）对雷帕霉素的敏感性，这支持了FA−癌细胞存在基于代谢的治疗脆弱性。 结论：这些发现揭示了FA通路在抑制mTOR信号传导中的新功能，并确定mTOR抑制可作为靶向治疗FA−型HNSCC的潜在策略。

原文链接：

The Fanconi Anemia Pathway Inhibits mTOR Signaling and Prevents Accelerated Translation in Head and Neck Cancer Cells