Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma
Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma
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DOI：
10.4161/cc.8.3.7643
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发表时间：
2009-02-01
期刊：
影响因子：
4.3
通讯作者：
Workman, Paul
中科院分区：
文献类型：
--
作者：
Guillard, Sandrine;Clarke, Paul A.;Workman, Paul
神经胶质瘤是预后不良的原发性脑肿瘤，其表现出磷脂酰肌醇3-激酶（PI 3激酶）信号传导的频繁异常。我们研究了亚型选择性I类PI 3激酶和mTOR抑制剂PI-103在人脑胶质瘤细胞中作用的分子机制。定量PI-103对PI 3激酶途径的有效抑制作用。PI-103和mTOR抑制剂雷帕霉素均抑制核糖体蛋白S6磷酸化，但PI 3激酶途径的上游组分的反应存在明显差异，例如Thr 308-AKT的磷酸化，其被PI-103而不是雷帕霉素抑制。基因表达谱鉴定了编码细胞周期和胆固醇代谢调节因子的基因的表达改变，以及由胰岛素或IGF 1信号传导、雷帕霉素治疗或营养饥饿调节的基因。PI-103降低G（1）/S期进程的正调节因子的表达，并增加细胞周期负调节因子p27（kip 1）的表达。PI-103介导的可逆G（1）细胞周期阻滞发生，无显著凋亡，与检测到的基因表达改变一致。PI-103诱导空泡化和LC-3 i至LC-3 ii的加工，这是自噬反应的特征。与PI-103相反，LY 294002和PI-387诱导细胞凋亡，表明可能的脱靶效应。PI-103与用于治疗胶质瘤的细胞毒性剂，即长春新碱、BCNU和替莫唑胺协同或相加地相互作用。与单独治疗相比，PI-103与替莫唑胺的组合显著改善了U87 MG人胶质瘤异种移植物的反应。我们的研究结果支持具有PI-103样特征的PI 3激酶抑制剂作为治疗胶质瘤的治疗剂的治疗潜力。
Gliomas are primary brain tumors with poor prognosis that exhibit frequent abnormalities in phosphatidylinositol 3-kinase (PI3 kinase) signaling. We investigated the molecular mechanism of action of the isoform-selective class I PI3 kinase and mTOR inhibitor PI-103 in human glioma cells. The potent inhibitory effects of PI-103 on the PI3 kinase pathway were quantified. PI-103 and the mTOR inhibitor rapamycin both inhibited ribosomal protein S6 phosphorylation but there were clear differences in the response of upstream components of the PI3 kinase pathway, such as phosphorylation of Thr308-AKT, that were inhibited by PI-103 but not rapamycin. Gene expression profiling identified altered expression of genes encoding regulators of the cell cycle and cholesterol metabolism, and genes modulated by insulin or IGF1 signaling, rapamycin treatment or nutrient starvation. PI-103 decreased expression of positive regulators of G(1)/S phase progression and increased expression of the negative cell cycle regulator p27(kip1). A reversible PI-103-mediated G(1) cell cycle arrest occurred without significant apoptosis, consistent with the altered gene expression detected. PI-103 induced vacuolation and processing of LC-3i to LC-3ii, which are features of an autophagic response. In contrast to PI-103, LY294002 and PI-387 induced apoptosis, indicative of likely off-target effects. PI-103 interacted synergistically or additively with cytotoxic agents used in the treatment of glioma, namely vincristine, BCNU and temozolomide. Compared to individual treatments, the combination of PI-103 with temozolomide significantly improved the response of U87MG human glioma xenografts. Our results support the therapeutic potential for PI3 kinase inhibitors with a PI-103-like profile as therapeutic agents for the treatment of glioma.