KiSS-1/G protein-coupled receptor 54 metastasis suppressor pathway increases myocyte-enriched calcineurin interacting protein 1 expression and chronically inhibits calcineurin activity

J Clin Endocrinol Metab. 2005 Sep;90(9):5432-40. doi: 10.1210/jc.2005-0963. Epub 2005 Jul 5.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcineurin Inhibitors*
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • DNA-Binding Proteins
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Kisspeptins
  • Muscle Proteins / metabolism*
  • Neoplasm Metastasis* / prevention & control
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Protein Kinase C / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptors, G-Protein-Coupled
  • Receptors, Kisspeptin-1
  • Receptors, Neuropeptide / metabolism*
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / physiopathology
  • Thyroid Neoplasms / secondary
  • Time Factors
  • Tumor Suppressor Proteins
  • Up-Regulation

Substances

  • Calcineurin Inhibitors
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • KISS1 protein, human
  • KISS1R protein, human
  • Kisspeptins
  • Muscle Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • RCAN1 protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Kisspeptin-1
  • Receptors, Neuropeptide
  • Tumor Suppressor Proteins
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases