AIMS: Although metformin has antitumor effects, the detailed mechanism of action, particularly with respect to the cellular responses mediated through G protein-coupled receptors (GPCRs), remains unclear. METHODS AND RESULTS: Here, we assayed a panel of 200 GPCRs in cells treated with metformin and reported that signaling through several receptors, including lysophosphatidic acid (LPA) receptors, was suppressed. Metformin significantly attenuated LPA-induced intracellular Ca CONCLUSIONS: These results indicate that the inhibition of LPA receptor signaling by metformin, especially the consequent suppression of LPAR3-mediated cell migration, may contribute to the antitumor effects of metformin.