Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 8, Pages 2835-2840Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0813351106
Keywords
GSK3 beta; lithium; mTOR; phosphatidylinositol 3-kinase; cancer
Categories
Funding
- Avon Foundation
- Mary Kay Ash Charitable Foundation
- Stewart Trust Fund
- National Institutes of Health [CA109274, CA88843, T32 CA09071-27]
- Flight Attendant Medical Research Institute (FAMRI)
- Breast Cancer Research Foundation
- Department of Defense Breast Cancer Research Program Predoctoral Fellowship Award [W81XWH-06-1-0325]
- NIH [T32DK067872]
- Yasuda Medical Research Foundation
- Kanzawa Medical Research Foundation
- American Society of Clinical Oncology's Young Investigator Award
- Susan G. Komen Foundation Postdoctoral Fellowship Award
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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 GSK3 beta phosphorylation. Paradoxically, the GSK3 beta 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 GSK3 beta 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 GSK3 beta 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.
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