突变型PIK3CA促进人类癌细胞的生长和侵袭。

Mutant PIK3CA promotes cell growth and invasion of human cancer cells.

作者信息

Samuels Yardena, Diaz Luis A, Schmidt-Kittler Oleg, Cummins Jordan M, Delong Laura, Cheong Ian, Rago Carlo, Huso David L, Lengauer Christoph, Kinzler Kenneth W, Vogelstein Bert, Velculescu Victor E

机构信息

The Sidney Kimmel Comprehensive Cancer Center and The Howard Hughes Medical Institute, The Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA.

出版信息

Cancer Cell. 2005 Jun;7(6):561-73. doi: 10.1016/j.ccr.2005.05.014.

DOI:10.1016/j.ccr.2005.05.014

PMID:15950905

Abstract

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.

摘要

PIK3CA在多种人类癌症中发生突变，但这些突变的功能影响尚未明确。为了评估PIK3CA改变的后果，通过基因靶向在结肠直肠癌（CRC）细胞中使两种最常见的突变失活。对这些细胞的生化分析表明，突变型PIK3CA选择性地调节AKT以及叉头转录因子FKHR和FKHRL1的磷酸化。PIK3CA突变在标准条件下对生长影响不大，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处理可消除PIK3CA信号传导，并优先抑制PIK3CA突变细胞的生长。这些数据对携带PIK3CA改变的癌症治疗具有重要意义。