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 GSK3beta phosphorylation. Paradoxically, the GSK3beta 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 GSK3beta 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 GSK3beta 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.
journal_name
Proc Natl Acad Sci U S Aauthors
Gustin JP,Karakas B,Weiss MB,Abukhdeir AM,Lauring J,Garay JP,Cosgrove D,Tamaki A,Konishi H,Konishi Y,Mohseni M,Wang G,Rosen DM,Denmeade SR,Higgins MJ,Vitolo MI,Bachman KE,Park BHdoi
10.1073/pnas.0813351106subject
Has Abstractpub_date
2009-02-24 00:00:00pages
2835-40issue
8eissn
0027-8424issn
1091-6490pii
0813351106journal_volume
106pub_type
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