Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, Jiangsu, China.
Department of Laboratory Medicine, The Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu, China.
Int Immunopharmacol. 2023 Jan;114:109595. doi: 10.1016/j.intimp.2022.109595. Epub 2022 Dec 19.
Methotrexate (MTX) is used to treat rheumatoid arthritis, acute leukemia, and psoriasis. MTX can cause certain side effects, such as myelosuppression, while the exact mechanism of myelosuppression caused by MTX is unknown. Notch signaling pathway has been considered to be essential to regulate hematopoietic stem cell (HSC) regeneration and homeostasis, thus contributing to bone marrow hematopoiesis. However, whether MTX affects Notch signaling remains unexplored. Here, our study provides evidence that MTX strongly suppresses the Notch signaling pathway. We found that MTX inhibited the interaction between Nedd4 with Numb, thus restricting K48-linked polyubiquitination of Numb and stabilizing Numb proteins. This in turn inhibited the Notch signaling pathway by reducing Notch1 protein levels. Interestingly, we found that a monomeric drug, Triptolide, is capable of alleviating the inhibitory effect of MTX on Notch signaling pathway. This study promotes our understanding of MTX-mediated regulation of Notch signaling and could provide ideas to alleviate MTX-induced myelosuppression.
甲氨蝶呤（MTX）用于治疗类风湿性关节炎、急性白血病和银屑病。MTX 可引起某些副作用，如骨髓抑制，而 MTX 引起骨髓抑制的确切机制尚不清楚。Notch 信号通路被认为对调节造血干细胞（HSC）的再生和稳态至关重要，从而有助于骨髓造血。然而，MTX 是否影响 Notch 信号通路仍未被探索。在这里，我们的研究提供了证据表明 MTX 强烈抑制 Notch 信号通路。我们发现 MTX 抑制了 Nedd4 与 Numb 之间的相互作用，从而限制了 Numb 的 K48 连接多泛素化和 Numb 蛋白的稳定。这反过来通过降低 Notch1 蛋白水平抑制了 Notch 信号通路。有趣的是，我们发现一种单体药物雷公藤内酯醇能够缓解 MTX 对 Notch 信号通路的抑制作用。这项研究促进了我们对 MTX 介导的 Notch 信号调节的理解，并为缓解 MTX 诱导的骨髓抑制提供了思路。
