UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093 USA.
Emory University School of Medicine, Atlanta, GA USA.
Cancer Cell Int. 2014 Nov 12;14(1):105. doi: 10.1186/s12935-014-0105-9. eCollection 2014.
Growth factor mediated activation of RAS-MAP-kinase and PI3-kinase-AKT pathways are critical for the pathogenesis of glioblastoma. The attenuation of PI3-kinase/AKT signaling will be effective in regulating the tumorigenic phenotypes of the glioma cells.
Glioma cells derived from the brain of the (12) V-Ha-Ras transgenic mice were used to study the effect of PI-3 kinase inhibitor SF1126 on activation of AKT and ERK signaling, proliferation, vitronectin mediated migration and changes in the distribution of cortical actin on vitronectin in the glioma cells in vitro. The anti-tumor effects of SF1126 were also tested in vivo using pre-established tumors (subcutaneous injection of the glioma cells from (12) V-Ha-Ras transgenic mice) in a mouse xenograft model.
Our results demonstrate that treatment of LacZ+, GFAP + and PCNA + (12) V-Ras Tg transformed astrocytes with SF1126 and LY294002 blocked the activation of AKT as well as EGF-induced phospho-ERK. Most notably, treatment of SF1126 blocked integrin-dependent migration in transwell and scratch assays and caused a significant change in the organization and distribution of cortical actin on vitronectin in the glioma cells. Moreover, SF1126 treatment inhibited in vitro proliferation of these cells and in vivo growth of pre-established subcutaneous tumors in a xenograft model.
The present study validate the potent anti-proliferative and anti-migratory activity of SF1126, in a V(12) Ras oncogene driven glioma model and suggest that this effect is mediated potentially through a combined attenuation of PI3-kinase and MAP-kinase signaling pathways.
生长因子介导的 RAS-MAP-激酶和 PI3-激酶-AKT 途径的激活对于神经胶质瘤的发病机制至关重要。PI3-激酶/AKT 信号的衰减将有效地调节神经胶质瘤细胞的致瘤表型。
使用源自 12V-Ha-Ras 转基因小鼠大脑的神经胶质瘤细胞来研究 PI-3 激酶抑制剂 SF1126 对 AKT 和 ERK 信号转导、增殖、纤连蛋白介导的迁移以及神经胶质瘤细胞在纤连蛋白上皮质肌动蛋白分布变化的影响。SF1126 的抗肿瘤作用也在体内使用预先建立的肿瘤（皮下注射 12V-Ha-Ras 转基因小鼠的神经胶质瘤细胞）在小鼠异种移植模型中进行了测试。
我们的结果表明，用 SF1126 和 LY294002 处理 LacZ+、GFAP+和 PCNA+（12）V-Ras Tg 转化的星形胶质细胞可阻断 AKT 的激活以及 EGF 诱导的磷酸化 ERK。值得注意的是，SF1126 处理阻断了整合素依赖性迁移的 Transwell 和划痕试验，并导致神经胶质瘤细胞在纤连蛋白上皮质肌动蛋白的组织和分布发生显著变化。此外，SF1126 处理抑制了这些细胞的体外增殖和异种移植模型中预先建立的皮下肿瘤的体内生长。
本研究验证了 SF1126 在 V(12)Ras 癌基因驱动的神经胶质瘤模型中的强大的抗增殖和抗迁移活性，并表明这种作用可能是通过同时衰减 PI3-激酶和 MAP-激酶信号通路介导的。
