The antibiotic drug trimethoprim suppresses tumour growth and metastasis via targeting Snail
The antibiotic drug trimethoprim suppresses tumour growth and metastasis via targeting Snail
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DOI：
10.1111/bph.15763
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发表时间：
2022-03-15
影响因子：
7.3
通讯作者：
Fu, Rong
中科院分区：
文献类型：
--
作者：
Ren, Bo-Xue;Li, Yang;Fu, Rong
背景与目的锌指转录因子Snail在许多人类癌症中异常激活，并与不良预后密切相关。作为一种转录因子，蜗牛一直被认为是“不可药物”的靶标。在这里，我们确定了一种有效的小分子蜗牛抑制剂，即甲氧苄啶，并研究了其潜在的抗肿瘤作用和潜在的机制。实验方法通过分子对接、生物层干涉、免疫印迹、免疫沉淀、qRT-PCR、pull-down和环己亚胺追脉等方法，揭示甲氧苄啶对蜗牛蛋白的抑制作用及其分子机制。通过多种细胞实验和动物模型测试了甲氧苄啶靶向蜗牛的抗增殖和抗转移作用。本研究通过对蜗牛的靶向作用，鉴定了抗菌药物甲氧苄啶是一种有效的抗肿瘤药物。分子模型分析预测，甲氧苄氨嘧啶直接结合到蜗牛蛋白的精氨酸-174口袋上。我们进一步发现甲氧苄氨嘧啶强烈阻断蜗牛与creb结合蛋白(CBP)/p300的相互作用，从而抑制蜗牛的乙酰化，并通过泛素-蛋白酶体途径促进蜗牛的降解。此外，甲氧苄氨嘧啶通过特异性靶向蜗牛，在体外充分抑制癌细胞的增殖、上皮-间质转化（EMT）和迁移。更重要的是，甲氧苄氨嘧啶有效地减少了蜗牛驱动的肿瘤生长和转移到肺、骨和肝等重要器官。结论和意义这些发现首次表明，甲氧苄啶通过靶向Snail抑制肿瘤生长和转移。本研究为进一步了解甲氧苄啶的抗癌作用提供了新的思路，并为临床治疗提供了一种潜在的抗癌药物。
Background and Purpose The zinc finger transcription factor Snail is aberrantly activated in many human cancers and strongly associated with poor prognosis. As a transcription factor, Snail has been traditionally considered an 'undruggable' target. Here, we identified a potent small-molecule inhibitor of Snail, namely trimethoprim, and investigated its potential antitumour effects and the underlying mechanisms. Experimental Approach The inhibitory action of trimethoprim on Snail protein and the related molecular mechanisms were revealed by molecular docking, biolayer interferometry, immunoblotting, immunoprecipitation, qRT-PCR, pull-down and cycloheximide pulse-chase assays. The anti-proliferative and anti-metastatic effects of trimethoprim via targeting Snail were tested in multiple cell-based assays and animal models. Key Results This study identified trimethoprim, an antimicrobial drug, as a potent antitumour agent via targeting Snail. Molecular modelling analysis predicted that trimethoprim directly binds to the arginine-174 pocket of Snail protein. We further discovered that trimethoprim strongly interrupts the interaction of Snail with CREB-binding protein (CBP)/p300, which consequently suppresses Snail acetylation and promotes Snail degradation through the ubiquitin-proteasome pathway. Furthermore, trimethoprim sufficiently inhibited the proliferation, epithelial-mesenchymal transition (EMT) and migration of cancer cells in vitro via specifically targeting Snail. More importantly, trimethoprim effectively reduced Snail-driven tumour growth and metastasis to vital organs such as lung, bone and liver. Conclusions and Implications These findings indicate, for the first time, that trimethoprim suppresses tumour growth and metastasis via targeting Snail. This study provides insights for a better understanding of the anticancer effects of trimethoprim and offers a potential anticancer therapeutic agent for clinical treatment.