The inhibition of transforming growth factor-β1 (TGF-β1) signaling by targeting TGF-β receptor 1 (TβR1) has been considered as an ideal approach for the prevention of pancreatic cancer metastasis. Utilizing a pharmacophore model for TβR1 inhibitors, candidate compounds with the potential TβR1 binding ability were screened from the U.S. Food and Drug Administration (FDA) database, and riboflavin (RF) with a highest fit value was chosen to investigate its binding ability to TβR1 and effect on TGF-β1 signaling in pancreatic cancer cells. Molecular docking and cellular thermal shift assay (CETSA) proved that RF at pharmacological concentrations could directly bind to TβR1. Further studies showed that pharmacological concentrations of RF could block TGF-β1 signaling, suppress the migration and invasion, and prevent epithelial-mesenchymal transition (EMT) process of pancreatic cancer cells in the absence or presence of TGF-β1 stimulation, indicating that RF presented anti-metastatic effect in pancreatic cancer cells. Knockdown of TβR1 could significantly attenuate the effects of RF on the migration and EMT process in pancreatic cancer cells, further confirming that the anti-metastatic effect of RF was achieved by blocking TGF-β1 signaling after binding to TβR1. Moreover, in a mouse model of pancreatic cancer metastasis, it was certified that RF administration could block lung and liver metastases, TGF-β1 signaling and EMT process of pancreatic cancer . In summary, our findings showed that RF could block TGF-β1 signaling by directly binding to TβR1, thereby suppressing the metastasis of pancreatic cancer cells by inhibiting EMT process both and .

中文翻译：

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核黄素通过靶向 TGF-β 受体 1 预防胰腺癌转移

通过靶向TGF-β受体1（TβR1）抑制转化生长因子-β1（TGF-β1）信号传导被认为是预防胰腺癌转移的理想方法。利用TβR1抑制剂的药效团模型，从美国食品药品监督管理局（FDA）数据库中筛选出具有潜在TβR1结合能力的候选化合物，并选择拟合值最高的核黄素（RF）来研究其与TβR1的结合能力对胰腺癌细胞中 TGF-β1 信号传导的影响。分子对接和细胞热位移分析（CETSA）证明药理学浓度的RF可以直接与TβR1结合。进一步的研究表明，药理学浓度的RF可以阻断TGF-β1信号传导，抑制迁移和侵袭，并在不存在或存在TGF-β1刺激的情况下阻止胰腺癌细胞的上皮间质转化（EMT）过程，表明RF呈现对胰腺癌细胞具有抗转移作用。敲低TβR1可以显着减弱RF对胰腺癌细胞迁移和EMT过程的影响，进一步证实RF的抗转移作用是通过与TβR1结合后阻断TGF-β1信号传导来实现的。此外，在胰腺癌转移的小鼠模型中，证明射频给药可以阻断胰腺癌的肺转移和肝转移、TGF-β1信号传导和EMT过程。总之，我们的研究结果表明，RF 可以通过直接与 TβR1 结合来阻断 TGF-β1 信号传导，从而通过抑制 EMT 过程来抑制胰腺癌细胞的转移。