Mutant PIK3CA promotes cell growth and invasion of human cancer cells.
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.
Samuels
Yardena
Y
The Sidney Kimmel Comprehensive Cancer Center and The Howard Hughes Medical Institute, The Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA.
Diaz
Luis A
LA
Schmidt-Kittler
Oleg
O
Cummins
Jordan M
JM
Delong
Laura
L
Cheong
Ian
I
Rago
Carlo
C
Huso
David L
DL
Lengauer
Christoph
C
Kinzler
Kenneth W
KW
Vogelstein
Bert
B
Velculescu
Victor E
VE
D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D018390:Gene Targeting; D006133:Growth Substances / Q000172:deficiency; D006801:Humans; D007328:Insulin / Q000172:deficiency; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D051017:Apoptosis Regulatory Proteins; D002867:Chromones; D058534:Class I Phosphatidylinositol 3-Kinases; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006133:Growth Substances; D007328:Insulin; D008562:Membrane Glycoproteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C484760:PIK3CA protein, human; C494918:AKT1 protein, human