Yang et al. determined that colon cancer cell lines proliferate in response to exposure to lysophosphatidic acid (LPA), with HCT116 and LS174T being the most responsive. Using siRNA, the authors determined that the proliferative response was mediated by two of the three LPA receptors, LPA2 and LPA3. Tumor growth in xenografted nude mice was also inhibited for HCT116 cells in which LPA2 or LPA3 was knocked down. LPA appeared to act through the β-catenin pathway in that siRNA for β-catenin resulted in inhibition of the proliferative response to LPA. Further support came from experiments showing that, in HCT116 cells, LPA stimulated phosphorylation of glycogen synthesis kinase 3β (GSK-3β), nuclear accumulation of β-catenin, and activation of β-catenin reporter gene and endogenous gene targets, such as those encoding c-myc and cyclin D1. Inhibitors of protein kinase C (PKC) blocked the LPA-mediated activation of the β-catenin pathway and cell proliferation, whereas phorbol esters, PKC activators, stimulated both processes. This suggested that coupling to Gαq is responsible for mediating LPA receptor to β-catenin signaling. Analysis of HeLa transfected with LPA2 or LPA3 indicated that both receptors coupled to the β-catenin pathway. Activation of the β-catenin pathway through LPA may contribute to colorectal cancer, and the LPA receptor antagonists may be therapeutically effective. Furthermore, these results provide more evidence for additional activators of the β-catenin pathway besides Wnt.
M. Yang, W. W. Zong, N. Srivastava, A. Slavin, J. Yang, T. Hoey, S. An, G protein-coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the β-catenin pathway. Proc. Natl. Acad. Sci. U.S.A. 102, 6027-6032 (2005). [Abstract] [Full Text]