G protein-coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the {beta}-catenin pathway.
Recent studies suggest that lysophosphatidic acid (LPA) and its G protein-coupled receptors (GPCRs) LPA(1), LPA(2), or LPA(3) may play a role in the development of several types of cancers, including colorectal cancer. However, the specific receptor subtype(s) and their signal-transduction pathways responsible for LPA-induced cancer cell proliferation have not been fully elucidated. We show by specific RNA interference (RNAi) that LPA(2) and LPA(3) but not LPA(1) are targets for LPA-induced proliferation of HCT116 and LS174T colon cancer cells. We determined that LPA-induced colon cancer cell proliferation requires the beta-catenin signaling pathway, because knockdown of beta-catenin by RNAi abolished LPA-induced proliferation of HCT116 cells. Moreover, LPA activates the main signaling events in the beta-catenin pathway: phosphorylation of glycogen synthase kinase 3beta (GSK3beta), nuclear translocation of beta-catenin, transcriptional activation of T cell factor (Tcf)/lymphoid-enhancer factor (Lef), and expression of target genes. Inhibition of conventional protein kinase C (cPKC) blocked the effects, suggesting its involvement in LPA-induced activation of the beta-catenin pathway. Thus, LPA(2) and LPA(3) signal the proliferation of colon cancer cells through cPKC-mediated activation of the beta-catenin pathway. These results link LPA and its GPCRs to cancer through a major oncogenic signaling pathway.
Yang
Ming
M
Department of Biology, Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Zhong
Wendy W
WW
Srivastava
Neelam
N
Slavin
Anthony
A
Yang
Jianxin
J
Hoey
Timothy
T
An
Songzhu
S
D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D015534:Trans-Activators; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D019204:GTP-Binding Proteins; C032881:lysophosphatidic acid