Abstract
Cell migration is a critical component of diverse biological phenomena in both physiological and pathological conditions. Sphingosine-1-phosphate (S1P) has attracted attention as a unique plasma-derived lysophospholipid mediator that either stimulates or inhibits cell migration. Recent studies including our own have disclosed several G protein-coupled receptor (GPCR) subtypes for S1P. These include S1P2/Edg5/AGR16, which we originally cloned as an orphan receptor and identified as the first GPCR that negatively regulates cell migration. Inhibition of a small G protein Rac at the site downstream of Rho activation is a mechanism for S1P2-mediated inhibition of migration. In sharp contrast, S1P1/Edg1 and S1P3/Edg3 mediate activation of Rac and chemotaxis in response to S1P through the Gi-PI 3-kinase pathway. S1P inhibits migration and invasion in vitro of mouse B16 melanoma cells by acting through endogenously expressed S1P2. S1P dose-dependently inhibits melanoma formation after subcutaneous inoculation, and lung metastasis after intravenous injection in vivo, with potentiation of S1P inhibition by S1P2 overexpression. By contrast, overexpression of either S1P1 or S1P3 in B16 cells results in stimulation of migration and invasion in vitro, and aggravation of tumor formation and metastasis in vivo in S1P dependent manners. These results provide the first evidence for GPCR subtype-specific, bi-directional regulation of tumor cell behaviors, raising a novel therapeutic strategy for cancer. [Jpn J Physiol 55 Suppl:S82 (2005)]
