BACKGROUND:Intracellular signaling responsible for gastrin-releasing peptide (GRP) receptor-mediated neovascularization is not clearly understood. We sought to determine the cellular mechanisms involved in the GRP receptor regulation of vascular endothelial growth factor (VEGF) release in neuroblastoma cells. MATERIALS AND METHODS:BE(2)-C cells were treated with bombesin (BBS), the amphibian equivalent of GRP, Phorbol myristate acetate (PMA) a PKC agonist, or GF109293X (GFX), and analyses were performed for VEGF secretion, phosphorylated protein kinase B (AKT), extracellular signal-regulated kinases (ERK) and protein kinase D (PKD) expression. RESULTS:BBS rapidly increased VEGF secretion at 30 min. Pre-treatment with PMA alone produced similar results; this effect was synergistic with the addition of GRP. Conversely, GFX blocked PMA-stimulated increase in VEGF secretion. Immunofluorescent staining for VEGF correlated to BBS, PMA and GFX. CONCLUSION:PKC is critically responsible for rapid VEGF secretion by GRP receptor signaling in neuroblastoma cells. Inhibition of VEGF significantly reduced GRP-mediated cell proliferation, suggesting its crucial role in neuroblastoma tumorigenesis.

译文

背景:负责胃泌素释放肽(GRP)受体介导的新血管形成的细胞内信号传递尚不清楚。我们试图确定参与神经母细胞瘤细胞中血管内皮生长因子(VEGF)释放的GRP受体调节的细胞机制。
材料与方法:将BE(2)-C细胞用Bombesin(BBS),GRP的两栖类等效物,PKC激动剂或肉豆蔻酸肉豆蔻酸酯(PMA)或GF109293X(GFX)处理,并进行VEGF分泌,磷酸化的分析蛋白激酶B(AKT),细胞外信号调节激酶(ERK)和蛋白激酶D(PKD)的表达。
结果:BBS在30分钟时迅速增加了VEGF的分泌。仅用PMA进行预处理可获得相似的结果。该效果与添加GRP协同作用。相反,GFX阻止了PMA刺激的VEGF分泌增加。 VEGF的免疫荧光染色与BBS,PMA和GFX相关。
结论:PKC是神经母细胞瘤细胞中GRP受体信号传导快速分泌VEGF的关键原因。 VEGF的抑制显着降低了GRP介导的细胞增殖,表明其在神经母细胞瘤肿瘤发生中的关键作用。

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