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Knockin of mutant PIK3CA activates multiple oncogenic pathways
- Source :
- Proceedings of the National Academy of Sciences. 106:2835-2840
- Publication Year :
- 2009
- Publisher :
- Proceedings of the National Academy of Sciences, 2009.
-
Abstract
- The phosphatidylinositol 3-kinase subunit PIK3CA is frequently mutated in human cancers. Here we used gene targeting to “knock in” PIK3CA mutations into human breast epithelial cells to identify new therapeutic targets associated with oncogenic PIK3CA. Mutant PIK3CA knockin cells were capable of epidermal growth factor and mTOR-independent cell proliferation that was associated with AKT, ERK, and GSK3β phosphorylation. Paradoxically, the GSK3β inhibitors lithium chloride and SB216763 selectively decreased the proliferation of human breast and colorectal cancer cell lines with oncogenic PIK3CA mutations and led to a decrease in the GSK3β target gene CYCLIN D1 . Oral treatment with lithium preferentially inhibited the growth of nude mouse xenografts of HCT-116 colon cancer cells with mutant PIK3CA compared with isogenic HCT-116 knockout cells containing only wild-type PIK3CA . Our findings suggest GSK3β is an important effector of mutant PIK3CA , and that lithium, an FDA-approved therapy for bipolar disorders, has selective antineoplastic properties against cancers that harbor these mutations.
- Subjects :
- Class I Phosphatidylinositol 3-Kinases
Transplantation, Heterologous
Mutant
Mice, Nude
Breast Neoplasms
Biology
medicine.disease_cause
Glycogen Synthase Kinase 3
Mice
Phosphatidylinositol 3-Kinases
Cyclin D1
Nude mouse
Epidermal growth factor
Cell Line, Tumor
Gene knockin
medicine
Animals
Humans
Gene Knock-In Techniques
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Mammary Glands, Human
neoplasms
PI3K/AKT/mTOR pathway
Mutation
Glycogen Synthase Kinase 3 beta
Multidisciplinary
TOR Serine-Threonine Kinases
Gene targeting
Oncogenes
Biological Sciences
biology.organism_classification
Cancer research
Colorectal Neoplasms
Protein Kinases
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 106
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....6c87e9b38d65061d822f1d7ee0cfaa0b