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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Substitution
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Animals
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Apoptosis / genetics
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Apoptosis Regulatory Proteins
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Base Sequence
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Cell Line, Tumor
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Cell Movement / genetics
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Cell Proliferation*
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Chromones / pharmacology
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Class I Phosphatidylinositol 3-Kinases
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Enzyme Inhibitors / pharmacology
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Gene Targeting
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Growth Substances / deficiency
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Humans
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Insulin / deficiency
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Membrane Glycoproteins / physiology
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Mice
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Mice, Nude
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Morpholines / pharmacology
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Mutation
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Neoplasm Invasiveness / genetics
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Neoplasm Invasiveness / pathology*
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Phosphatidylinositol 3-Kinases / genetics*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Signal Transduction / drug effects
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TNF-Related Apoptosis-Inducing Ligand
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Necrosis Factor-alpha / physiology
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Xenograft Model Antitumor Assays / methods
Substances
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Apoptosis Regulatory Proteins
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Chromones
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DNA-Binding Proteins
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Enzyme Inhibitors
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FOXO1 protein, human
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FOXO3 protein, human
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Growth Substances
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Insulin
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Membrane Glycoproteins
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Transcription Factors
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Tumor Necrosis Factor-alpha
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt