Koichi Sato 1, Hideaki Ogasawara 2, Yuichi Ikeda 2, Hidetoshi Kumagai 2, Ryota Inoue 1, Takahiro Tsuno 1, Koichi Matsunaga 1, Emi Ishida 1, and Jun Shirakawa 1, 3, * (1. Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Japan: 2. Tanso Biosciences, Inc., Japan; 3. Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Japan; *Corresponding Author)
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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. 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 Ca2+ 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 Gq/11 inhibitor YM-254890 and metformin. In contrast, these inhibitors had minimal effects on the cell migration induced by epidermal growth factor. 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.
Paper information
The antitumor effects of metformin are potentially mediated through LPA receptor inhibition.
Koichi Sato, Hideaki Ogasawara, Yuichi Ikeda, Hidetoshi Kumagai, Ryota Inoue, Takahiro Tsuno, Koichi Matsunaga, Emi Ishida, and Jun Shirakawa
Diabetes Res Clin Pract. 2025 Mar 8:112082. doi: 10.1016/j.diabres.2025.112082.
Online URL
https://www.sciencedirect.com/science/article/pii/S0168822725001081
