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PNAS 102 (17): 6027-6032

Copyright © 2005 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

G protein-coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the β-catenin pathway

Ming Yang, Wendy W. Zhong, Neelam Srivastava, Anthony Slavin, Jianxin Yang, Timothy Hoey, and Songzhu An*

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

Received for publication July 23, 2004.

Abstract: 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 β-catenin signaling pathway, because knockdown of β-catenin by RNAi abolished LPA-induced proliferation of HCT116 cells. Moreover, LPA activates the main signaling events in the β-catenin pathway: phosphorylation of glycogen synthase kinase 3β (GSK3β), nuclear translocation of β-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 β-catenin pathway. Thus, LPA2 and LPA3 signal the proliferation of colon cancer cells through cPKC-mediated activation of the β-catenin pathway. These results link LPA and its GPCRs to cancer through a major oncogenic signaling pathway.

Key Words: colon cancer cell • G protein-coupled receptor

* To whom correspondence should be addressed. E-mail: san{at}amgen.com.

Communicated by David V. Goeddel, Amgen, Inc., South San Francisco, CA, February 25, 2005

Author contributions: T.H. and S.A. designed research; M.Y., W.W.Z., N.S., A.S., and J.Y. performed research; M.Y., A.S., and S.A. analyzed data; M.Y. and S.A. wrote the paper; and T.H. edited and commented on the manuscript.

Abbreviations: APC, adenomatous polyposis coli; cPKC, conventional protein kinase C; GPCR, G protein-coupled receptor; GSK3β, glycogen synthase kinase 3β; Lef, lymphoid-enhancer factor; LPA, lysophosphatidic acid; PMA, phorbol 12-myristate 13-acetate; siRNA, small interfering RNA; Tcf, T cell factor.

© 2005 by The National Academy of Sciences of the USA

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