Knockin of mutant PIK3CA activates multiple oncogenic pathways
0301 basic medicine
0303 health sciences
Glycogen Synthase Kinase 3 beta
Class I Phosphatidylinositol 3-Kinases
TOR Serine-Threonine Kinases
Mice, Nude
Breast Neoplasms
Oncogenes
3. Good health
Glycogen Synthase Kinase 3
Mice
Phosphatidylinositol 3-Kinases
03 medical and health sciences
Cell Line, Tumor
Mutation
Animals
Humans
Gene Knock-In Techniques
Phosphorylation
Colorectal Neoplasms
Extracellular Signal-Regulated MAP Kinases
Mammary Glands, Human
Protein Kinases
Proto-Oncogene Proteins c-akt
DOI:
10.1073/pnas.0813351106
Publication Date:
2009-02-07T05:06:11Z
AUTHORS (18)
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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (35)
CITATIONS (142)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....