Knockin of mutant PIK3CA activates multiple oncogenic pathways.
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.
Gustin
John P
JP
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Karakas
Bedri
B
Weiss
Michele B
MB
Abukhdeir
Abde M
AM
Lauring
Josh
J
Garay
Joseph P
JP
Cosgrove
David
D
Tamaki
Akina
A
Konishi
Hiroyuki
H
Konishi
Yuko
Y
Mohseni
Morassa
M
Wang
Grace
G
Rosen
D Marc
DM
Denmeade
Samuel R
SR
Higgins
Michaela J
MJ
Vitolo
Michele I
MI
Bachman
Kurtis E
KE
Park
Ben Ho
BH
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055879:Gene Knock-In Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014183:Transplantation, Heterologous
D058534:Class I Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C484760:PIK3CA protein, human; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse