Mutant PIK3CA promotes cell growth and invasion of human cancer cells.
Journal:
Cancer Cell 2005 JunAuthors:
Samuels Y, Diaz LA, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE
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 condition
...[more]s, 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.[less]
Mesh Headings:
Amino Acid Substitution, Animals, Apoptosis, Apoptosis Regulatory Proteins, Base Sequence, Cell Line, Tumor, Cell Movement, Cell Proliferation, Chromones, DNA-Binding Proteins, Enzyme Inhibitors, Forkhead Transcription Factors, Gene Targeting, Growth Substances, Humans, Insulin, Membrane Glycoproteins, Mice, Mice, Nude, Morpholines, Mutation, Neoplasm Invasiveness, Neoplasms, Experimental, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand, Transcription Factors, Tumor Necrosis Factor-alpha, Xenograft Model Antitumor Assays