Mutant PIK3CA promotes cell growth and invasion of human cancer cells
Mutant PIK3CA promotes cell growth and invasion of human cancer cells
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DOI：
10.1016/j.ccr.2005.05.014
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发表时间：
2005-06-01
期刊：
影响因子：
50.3
通讯作者：
Velculescu, VE
中科院分区：
文献类型：
--
作者：
Samuels, Y;Diaz, LA;Velculescu, VE
PIK3CA在多种人类癌症中发生突变，但这些突变的功能效应尚未确定。为了评估PIK3CA改变的后果，在结直肠癌（CRC）细胞中通过基因靶向使两种最常见的突变失活。这些细胞的生化分析表明，突变体PIK3CA选择性地调节AKT和叉头转录因子FKHR和FKHRL1的磷酸化。PIK3CA突变在标准条件下对生长几乎没有影响，但降低了细胞对生长因子的依赖性。PIK3CA突变导致细胞凋亡减弱并促进肿瘤侵袭。用PI3K抑制剂LY294002处理废除PIK3CA信号传导并优先抑制PIK3CA突变细胞的生长。这些数据对于治疗携带PIK3CA改变的癌症具有重要意义。
PIK3CA is mutated in diverse human cancers, but the functional effects of these mutations have not been defined. To evaluate the consequences of PIK3CA alterations, the two most common mutations were inactivated by gene targeting in colorectal cancer (CRC) cells. Biochemical analyses of these cells showed that mutant PIK3CA selectively regulated the phosphorylation of AKT and the forkhead transcription factors FKHR and FKHRL1. PIK3CA mutations had little effect on growth under standard conditions, but reduced cellular dependence on growth factors. PIK3CA mutations resulted in attenuation of apoptosis and facilitated tumor invasion. Treatment with the PI3K inhibitor LY294002 abrogated PIK3CA signaling and preferentially inhibited growth of PIK3CA mutant cells. These data have important implications for therapy of cancers harboring PIK3CA alterations.