Glioblastoma cell growth is suppressed by disruption of fibroblast growth factor pathway signaling
Glioblastoma cell growth is suppressed by disruption of fibroblast growth factor pathway signaling
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DOI：
10.1007/s11060-009-9885-5
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发表时间：
2009-09-01
影响因子：
3.9
通讯作者：
Riggins, Gregory J.
中科院分区：
文献类型：
--
作者：
Loilome, Watcharin;Joshi, Avadhut D.;Riggins, Gregory J.
据报道，成纤维细胞生长因子（FGF）信号传导途径刺激胶质母细胞瘤（GBM）生长。在这项工作中，我们评估了FGF 2，FGF受体（FGFR）和小分子抑制对在传统培养基中生长的GBM细胞或直接在干细胞培养基中培养的GBM细胞的影响。这些细胞系各自表达FGFR 1、FGFR 3和FGFR 4受体。FGF 2配体的添加在10个细胞系中的8个中显示出显著的生长刺激。通过中和FGF 2单克隆抗体破坏FGF信号传导和通过RNA干扰抑制FGFR 1均部分抑制细胞增殖。生长抑制在时间上与MAPK信号传导的减少相关。具有已知FGFR/VEGFR活性的受体酪氨酸激酶抑制剂PD 173074显示出可再现的生长抑制。PD 173074抑制生长的可能机制与AKT和MAPK（已知的致癌信号转导蛋白）磷酸化水平降低有关。还观察到细胞周期蛋白D1、细胞周期蛋白D2和CDK 4细胞周期调节剂的随后减少。我们的研究结果表明，FGF信号通路抑制作为单一疗法将减缓，但不会阻止胶质母细胞瘤细胞的生长。
The Fibroblast Growth Factor (FGF) signaling pathway is reported to stimulate glioblastoma (GBM) growth. In this work we evaluated the effect of FGF2, FGF receptor (FGFR), and small molecule inhibition on GBM cells grown in traditional media, or cultured directly in stem-cell media. These lines each expressed the FGFR1, FGFR3 and FGFR4 receptors. Addition of FGF2 ligand showed significant growth stimulation in 8 of 10 cell lines. Disruption of FGF signaling by a neutralizing FGF2 monoclonal antibody and FGFR1 suppression by RNA interference both partially inhibited cell proliferation. Growth inhibition was temporally correlated with a reduction in MAPK signaling. A receptor tyrosine kinase inhibitor with known FGFR/VEGFR activity, PD173074, showed reproducible growth inhibition. Possible mechanisms of growth suppression by PD173074 were implicated by reduced phosphorylation of AKT and MAPK, known oncogenic signal transducers. Subsequent reduction in the cyclin D1, cyclin D2 and CDK4 cell cycle regulators was also observed. Our results indicate that FGF signaling pathway inhibition as a monotherapy will slow, but not arrest growth of glioblastoma cells.