Ivanov Sergey M, Zgoda Victor G, Isakova Valeria A, Trukhanova Lyubov S, Poroikov Vladimir V, Shtil Alexander A
Institute of Biomedical Chemistry, 119121 Moscow, Russia.
Department of Bioinformatics, Pirogov Russian National Research Medical University, 117513 Moscow, Russia.
Cancers (Basel). 2024 Nov 30;16(23):4025. doi: 10.3390/cancers16234025.
Damage of the gastrointestinal mucosa is a major side effect of the anticancer drug 5-fluorouracil (5-FU). Insight into the molecular pathogenesis of 5-FU-induced gut mucositis is expected to justify the strategies of prophylaxis. We analyzed intestinal specimens obtained from Balb/c mice treated with 70 mg/kg 5-FU daily for up to 6 days. Manifestations of mucositis in the ileum and the colon included diarrhea, weight loss, and morphological lesions. The proteomic analysis revealed dozens of differentially expressed proteins governed by a set of master regulator proteins that regulated downstream pathways culminating in the complexes of specific transcription factors. Among the most important mechanisms of 5-FU-induced gut damage predicted by bioinformatics tools was stimulation of insulin-like growth factor 1 concomitant with inhibition of insulin receptor substrate 1, suggesting an involvement of the insulin pathway. Furthermore, the levels of 14-3-3γ protein and epinephrin B2 tyrosine kinase were interpreted as key inhibitory effects of 5-FU. These changes were detectable in the ileum as well as in the colon, pointing to the commonality of 5-FU responses across the gut. These results demonstrated a hierarchical network of gut injury mechanisms differentially regulated in the course of the emergence of 5-FU-induced mucositis.
胃肠道黏膜损伤是抗癌药物5-氟尿嘧啶（5-FU）的主要副作用。深入了解5-FU诱导的肠道黏膜炎的分子发病机制有望为预防策略提供依据。我们分析了从每天接受70 mg/kg 5-FU治疗长达6天的Balb/c小鼠获得的肠道标本。回肠和结肠黏膜炎的表现包括腹泻、体重减轻和形态学损伤。蛋白质组学分析揭示了数十种差异表达的蛋白质，这些蛋白质受一组主调节蛋白控制，这些主调节蛋白调节下游通路，最终形成特定转录因子的复合物。生物信息学工具预测的5-FU诱导肠道损伤的最重要机制之一是胰岛素样生长因子1的刺激与胰岛素受体底物1的抑制相伴，这表明胰岛素通路参与其中。此外，14-3-3γ蛋白和肾上腺素B2酪氨酸激酶的水平被解释为5-FU的关键抑制作用。这些变化在回肠和结肠中均可检测到，表明整个肠道对5-FU的反应具有共性。这些结果证明了在5-FU诱导的黏膜炎出现过程中差异调节的肠道损伤机制的层次网络。
