Knockin of mutant PIK3CA activates multiple oncogenic pathways |
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| Authors: | John P. Gustin Bedri Karakas Michele B. Weiss Abde M. Abukhdeir Josh Lauring Joseph P. Garay David Cosgrove Akina Tamaki Hiroyuki Konishi Yuko Konishi Morassa Mohseni Grace Wang D. Marc Rosen Samuel R. Denmeade Michaela J. Higgins Michele I. Vitolo Kurtis E. Bachman Ben Ho Park |
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| Affiliation: | aThe Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231; ;bDepartment of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218; and ;cThe Stewart and Marlene Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201 |
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| 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. |
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| Keywords: | GSK3β , lithium, mTOR, phosphatidylinositol 3-kinase, cancer |
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