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This version published online on July 5, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0963
A more recent version of this article appeared on September 1, 2005
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Submitted on May 2, 2005
Accepted on June 29, 2005

KiSS-1/GPR54 Metastasis Suppressor Pathway Increases MCIP-1 Expression and Chronically Inhibits Calcineurin Activity

Nikolaos Stathatos, Isabella Bordeau, Allan V. Espinosa, Motoyasu Saji, Vasily V. Vasko, Kenneth D. Burman MD, Constantine A. Stratakis, and Matthew D. Ringel*

The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio; Washington Hospital Center/MedStar Research Institute, Washington, DC; Uniformed Services University of the Health Sciences, Bethesda, MD; Section on Endocrinology and Genetics (SEGN), DEB, National Institute of Child Health and Development, NIH, Bethesda, MD

* To whom correspondence should be addressed. 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 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 PKC, ERK and PI3K 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 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 to primary tumors.

Conclusions: These data suggest a role for MCIP-1 and calcineurin inhibition in GPR54-mediated metastasis suppression in human cancers.
Key words: Thyroid Cancer • Metastin • TRB3 • DSCR1 • Calcipressin




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