The mechanism of action of the
metastasis suppressor KiSS1 and its receptor GPR54 is still incompletely characterized. Although the loss of KiSS1 expression by
tumor cells has been associated with a metastatic phenotype, the nature of the cellular target of the secreted
kisspeptins is unknown. Although an autocrine model of action has been generally assumed,
metastasis suppression by KiSS1 has also been shown in cells that do not express GPR54, suggesting a paracrine mechanism in which
kisspeptins affect cells in the metastatic niche. Activation of GPR54 was shown to inhibit cell motility and invasion of
tumor cells, induce the formation of stress fibers, and reduce the expression of
matrix metalloproteinase 9. We showed previously that the activation of GPR54 by
kisspeptin-10 suppressed CXCR4-mediated chemotaxis in response to
stromal cell-derived factor 1/CXCL12 and abolished the phosphorylation of Akt by CXCR4. We also demonstrated that activation of GPR54 inhibited Akt phosphorylation after the activation of
epidermal growth factor receptor and the
insulin receptor and triggered apoptosis in epithelial and lymphoid cell lines through a mechanism involving
extracellular signal-regulated kinase (ERK)
mitogen-activated protein kinase. We show here that the activation of GPR54 induced immediate and profound changes of cell morphology, including cytoplasmic condensation and formation of unpolarized plasma membrane protrusions. These events were dependent on Rho and
Rho-Associated Kinase (ROCK) activation. The activation of ROCK also contributed to GPR54-mediated apoptosis in 293 cells, and its effect was additive to and independent of ERK activation. These results suggest that RhoA and ROCK are additional key components of the antimetastatic effect of
kisspeptins.