Crosstalk between cannabinoid receptor 2 and lysophosphatidic acid receptor 5

Cannabinoid receptor 2 (CB₂) and lysophosphatidic acid receptor 5 (LPA₅) are both classified as G-protein coupled receptors (GPCRs) activated by bioactive lipids and are highly expressed in colon cancer cells. However, crosstalk between two receptors and its potential effects on cancer cell physiology have not been fully elucidated. In the present study, the results of bioluminescence resonance energy transfer analysis showed that, among the LPA receptors, CB₂ strongly and specifically interacted with LPA₅. Both receptors were co-localized in the plasma membrane in the absence of agonists, and the receptors were co-internalized upon activation of either receptor alone or both receptors together. We further investigated the effects of expression of both receptors on cell proliferation and migration, and the molecular mechanisms underlying these effects in HCT116 colon cancer cells. Co-expression of receptors significantly increased cell proliferation and migration by increasing Akt phosphorylation and tumor progression-related gene expression, whereas no such effect was seen upon expression of either receptor alone. These results suggest the possibility of physical and functional crosstalk between CB₂ and LPA₅.