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KiSS-1/G Protein-Coupled Receptor 54 Metastasis Suppressor Pathway Increases Myocyte-Enriched Calcineurin Interacting Protein 1 Expression and Chronically Inhibits Calcineurin Activity

The Ohio State University and Arthur G. James Comprehensive Cancer Center (N.S., A.V.E., M.S., V.V.V., M.D.R.), Columbus, Ohio 43210; Washington Hospital Center/MedStar Research Institute (N.S., V.V.V., K.D.B., M.D.R.), Washington, D.C. 20010; Uniformed Services University of the Health Sciences (V.V.V., M.D.R.), Bethesda, Maryland 20814; and Section on Endocrinology and Genetics (I.B., C.A.S.), DEB, National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Matthew D. Ringel, M.D., The Ohio State University, 445D McCampbell Hall, 1581 Dodd Drive, Columbus, Ohio 43210. E-mail: ringel.11{at}osu.edu.

Objective: 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.

Design and Results: 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.

Conclusions: These data suggest a role for MCIP-1 and calcineurin inhibition in GPR54-mediated metastasis suppression in human cancers.

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