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 mobilization in LPA receptor 1 (LPAR1)-, 2 (LPAR2)-, and 3 (LPAR3)-transfected rat hepatoma RH7777 cells. LPA treatment increased LPAR3-transfected RH7777 cell adhesion and migration. This response to LPA was attenuated by treatment with the G inhibitor YM-254890 and metformin. In contrast, these inhibitors had minimal effects on the cell migration induced by epidermal growth factor.
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.
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