Abstract
Kisspeptins (Kp), peptide products of the Kisspeptin-1 (KISS1) gene are endogenous ligands for a G protein-coupled receptor 54 (GPR54). Previous findings have shown that KISS1 acts as a metastasis suppressor in numerous cancers in humans. However, recent studies have demonstrated that an increase in KISS1 and GPR54 expression in human breast tumors correlates with higher tumor grade and metastatic potential. At present, whether or not Kp signaling promotes breast cancer cell invasiveness, required for metastasis and the underlying mechanisms, is unknown. We have found that kisspeptin-10 (Kp-10), the most potent Kp, stimulates the invasion of human breast cancer MDA-MB-231 and Hs578T cells using Matrigel-coated Transwell chamber assays and induces the formation of invasive stellate structures in three-dimensional invasion assays. Furthermore, Kp-10 stimulated an increase in matrix metalloprotease (MMP)-9 activity. We also found that Kp-10 induced the transactivation of epidermal growth factor receptor (EGFR). Knockdown of the GPCR scaffolding protein, β-arrestin 2, inhibited Kp-10-induced EGFR transactivation as well as Kp-10 induced invasion of breast cancer cells via modulation of MMP-9 secretion and activity. Finally, we found that the two receptors associate with each other under basal conditions, and FRET analysis revealed that GPR54 interacts directly with EGFR. The stability of the receptor complex formation was increased upon treatment of cells by Kp-10. Taken together, our findings suggest a novel mechanism by which Kp signaling via GPR54 stimulates breast cancer cell invasiveness.
Highlights
Kisspeptins (Kp) are peptide products of the metastasissuppressor KISS1 gene and are the endogenous ligands for G protein-coupled receptor 54 (GPR54), a Gq/11-coupled receptor [1,2,3]
We found that treatment of MDA-MB231 cells that express endogenous GPR54 [27] with either 10 or 100 nM of Kp-10 increases the secretion of matrix metalloprotease (MMP)-9 (Fig. 2D), revealing for the first time that Kp-10 signaling via GPR54 in breast cancer cells stimulates the secretion of matrix metalloprotease-9 (MMP-9)
Recent studies indicate that Kp signaling may correlate positively with breast tumor progression and metastatic potential [10,11], it is unknown whether Kp stimulate breast cancer cell invasiveness
Summary
Kisspeptins (Kp) are peptide products of the metastasissuppressor KISS1 gene and are the endogenous ligands for G protein-coupled receptor 54 (GPR54), a Gq/11-coupled receptor [1,2,3]. The shortest and most active KISS1 gene product is Kisspeptin-10 (Kp-10), a 10-residue peptide [3] In numerous cancers such as melanoma, pancreatic cancer, and gastric carcinoma, KISS1/GPR54 signaling is anti-metastatic [5,6]. GPR54 activity has been shown to repress matrix metalloprotease-9 (MMP-9) activity, increase production of tissue inhibitor of matrix metalloprotease-1 (TIMP-1), inhibit cell migration, and increase activity of focal adhesion kinase (FAK), leading to formation of excessive focal adhesions and stress fibres [3,4]. Activation of GPR54 by Kp has been shown to inhibit cell motility, proliferation, invasion, chemotaxis and metastasis [2,3,7,8,9]
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