Kisspeptin-10 inhibits bone-directed migration of GPR54-positive breast cancer cells: Evidence for a dose-window effect.

Abstract

OBJECTIVES:

The KiSS-1 gene product is absent or expressed at low level in metastatic breast cancer compared with their nonmetastatic counterparts. A deca-peptide derived from the KiSS-1 gene product, designated kisspeptin-10 (Kp-10), activates a receptor coupled to Gαq subunits (GPR54 or KiSS-1R). In this study we have analyzed whether Kp-10 treatment affects bone-directed migration of GPR54-positive breast cancer cells.

METHODS:

GPR54 expression was analyzed using immune cytochemistry. Bone-directed breast cancer cell invasion was measured by assessment of the breast cancer cell migration rate through an artificial basement membrane. Chemokine receptor CXCR4 and stromal cell-derived factor-1 (SDF-1) mRNA expression was quantified using semi-quantitative RT-PCR. CXCR4 protein expression and SDF-1 protein secretion were measured using the western blot technique.

RESULTS:

Breast cancer cell invasion was increased when cocultured with MG63 osteoblast-like cells. Treatment with KP-10 reduced the ability to invade a reconstituted basement membrane and to migrate in response to the cellular stimulus. This effect was significant in a dose-window of 10⁻⁹ M to 10⁻¹¹ M. Searching for the molecular mechanisms we found that KP-10 treatment significantly reduces expression of the chemokine receptor CXCR4 by the breast cancer cells. In addition, expression and secretion of its ligand SDF-1 by the MG63 cells were significantly reduced. Furthermore, SDF-1-induced CXCR4 signaling was down-regulated.

CONCLUSIONS:

These data represent the first report that KP-10 inhibits bone-directed migration of GPR54-positive breast cancer cells. In addition, we found evidence for a KP-10 dose-window effect. Furthermore, the SDF-1/CXCR4 system seems to be involved in the anti-migratory action of KP-10.

• Authors: Teresa Olbrich, Elke Ziegler, Gregor Türk, Antje Schubert, Günter Emons, Carsten Gründker
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 119 Issue 3 Pg. 571-8 (Dec 2010) ISSN: 1095-6859 [Electronic] United States
• PMID: 20832102 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• CXCR4 protein, human
• Chemokine CXCL12
• KISS1 protein, human
• KISS1R protein, human
• Kisspeptins
• RNA, Messenger
• Receptors, CXCR4
• Receptors, G-Protein-Coupled
• Receptors, Kisspeptin-1
• Tumor Suppressor Proteins
• Oncogene Protein v-akt

Topics

• Bone Neoplasms (pathology)
• Breast Neoplasms (metabolism, pathology)
• Cell Communication (drug effects, physiology)
• Cell Line, Tumor
• Cell Movement (drug effects, physiology)
• Chemokine CXCL12 (biosynthesis, genetics)
• Coculture Techniques
• Female
• Humans
• Immunohistochemistry
• Kisspeptins
• Oncogene Protein v-akt (metabolism)
• Osteoblastoma (pathology)
• Osteoblasts (pathology)
• Phosphorylation (drug effects)
• RNA, Messenger (biosynthesis, genetics)
• Receptors, CXCR4 (biosynthesis, genetics, metabolism)
• Receptors, G-Protein-Coupled (biosynthesis)
• Receptors, Kisspeptin-1
• Signal Transduction (drug effects)
• Tumor Suppressor Proteins (pharmacology)