解放军医学院学报2025，Vol.46Issue(3)：230-238,9.DOI:10.12435/j.issn.2095-5227.24120602
度洛西汀通过诱导G0/G1期细胞周期阻滞抑制神经胶质瘤生长的机制研究
Mechanism of duloxetine inhibiting glioma growth by inducing G0/G1 phase cell cycle arrest
摘要
Abstract
Background Previous studies have shown that duloxetine(DUL)exhibits cytotoxicity in lung and pancreatic cancer cells,but its effects and mechanisms in glioblastoma(GBM)remain unclear.Objective To investigate the anti-tumor effects of duloxetine on GBM and its potential mechanisms.Methods Human glioblastoma cell lines U87 and U251 were treated with duloxetine at different concentrations(10 μmol/L,20 μmol/L,30 μmol/L),with a blank control group and a 300 μmol/L temozolomide(TMZ)treatment group established as controls.CCK-8 and Transwell assays were used to evaluate the effects of duloxetine on cell proliferation,migration,and invasion.Flow cytometry was used to analyze changes in the cell cycle.Potential mechanisms were explored by transcriptome sequencing.The expression of S-phase kinase-associated protein 2(Skp2),p21,and p27 at both mRNA and protein levels was measured using qPCR and Western blotting.Molecular docking was performed using Autodock Vina to simulate the binding affinity between duloxetine and the Skp2 protein.Results Duloxetine significantly inhibited GBM cell proliferation,migration,and invasion(P<0.05).In U87 cells,the inhibition rates at 10,20,and 30 μmol/L of duloxetine were 18.06%±3.91%,47.37%±1.42%,and 64.85%±0.90%,respectively(P<0.001).Compared with the control group,duloxetine treatment markedly increased the proportion of U87 cells in the G0/G1 phase(64.76%±1.2%,72.18%±1.22%,and 79.03%±2.25%vs 55.72%±0.91%,P<0.001).RNA-seq and validation experiments demonstrated that duloxetine downregulated Skp2 mRNA and protein expression while upregulating p21 and p27 mRNA and protein levels(P<0.05).Molecular docking revealed that duloxetine exhibited high binding affinity with Skp2(-30.96 kJ/mol).Conclusion Duloxetine inhibits GBM cell proliferation,migration,and invasion,and induces G0/G1 cell cycle arrest by regulating the Skp2-p21/p27 signaling pathway,providing a new perspective for GBM treatment.关键词
度洛西汀/胶质母细胞瘤/细胞增殖/细胞周期/S期蛋白激酶相关蛋白Key words
duloxetine/glioblastoma/cell proliferation/cell cycle/S-phase kinase-associated protein分类
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曾巽凌,郑湘锦,李晨,李悦,陈孟莉..度洛西汀通过诱导G0/G1期细胞周期阻滞抑制神经胶质瘤生长的机制研究[J].解放军医学院学报,2025,46(3):230-238,9.基金项目
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