期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2005
卷号：102
期号：17
页码：6027-6032
DOI：10.1073/pnas.0501535102
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Recent studies suggest that lysophosphatidic acid (LPA) and its G protein-coupled receptors (GPCRs) LPA1, LPA2, or LPA3 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 LPA2 and LPA3 but not LPA1 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 3{beta} (GSK3{beta}), 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, LPA2 and LPA3 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.
关键词：colon cancer cell ; G protein-coupled receptor
