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Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6027-32. Epub 2005 Apr 18.

G protein-coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the {beta}-catenin pathway.

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  • 1Department of Biology, Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.

Abstract

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.

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