The study shows that the peptide kisspeptin‑10 (called metastin) can bind to a receptor (GPR54) on thyroid cancer cells, trigger signaling pathways, and eventually raise levels of a protein (MCIP‑1) that blocks another protein called calcineurin. This chain of events slows down cancer cell growth and movement, suggesting a role in preventing cancer spread, but the work was done in cell cultures, not people.

Tumor metastasis is a critical determinant of death from cancer. Metastin, a product of the KiSS-1 gene, is an endogenously expressed metastasis suppressor that is the ligand for G protein-coupled receptor 54 (GPR54), a Gq/11-coupled receptor. In the present study, our goal was to define the basis of GPR54 action using thyroid cancer cells as a model. We used GPR54-null thyroid cancer cells to create a stable GPR54 overexpression model. Cell growth and cell migration of the GPR54-expressing lines were inhibited by recombinant metastin, and metastin stimulated the protein kinase C, ERK, and phosphatidylinositol-3-kinase pathways. To identify metastin-regulated genes, we performed microarray analyses using RNA isolated from GPR54 stable transfectants before and after 1 and 24 h of metastin stimulation. Consistent increases in expression of the gene encoding myocyte-enriched calcineurin interacting protein 1 (MCIP-1), an inhibitor of calcineurin, were identified and confirmed using real-time RT-PCR and Western blot. Functionally, metastin treatment of GPR54-expressing cells initially increased calcineurin activity, followed by a prolonged reduction in calcineurin activity for 24 and 48 h, consistent with the pattern of MCIP-1 expression. In addition, treatment with cyclosporin A, a calcineurin inhibitor, blocked cell migration. Lymph node metastasis in papillary thyroid cancers demonstrated loss of MCIP-1 expression in comparison with primary tumors. These data suggest a role for MCIP-1 and calcineurin inhibition in GPR54-mediated metastasis suppression in human cancers.