GnRH-(1-5) activates matrix metallopeptidase-9 to release epidermal growth factor and promote cellular invasion.
In the extracellular space, the gonadotropin-releasing hormone (GnRH) is metabolized by the zinc metalloendopeptidase EC3.4.24.15 (EP24.15) to form the pentapeptide, GnRH-(1-5). GnRH-(1-5) diverges in function and mechanism of action from GnRH in the brain and periphery. GnRH-(1-5) acts on the orphan G protein-coupled receptor 101 (GPR101) to sequentially stimulate epidermal growth factor (EGF) release, phosphorylate the EGF receptor (EGFR), and facilitate cellular migration. These GnRH-(1-5) actions are dependent on matrix metallopeptidase (MMP) activity. Here, we demonstrated that these GnRH-(1-5) effects are dependent on increased MMP-9 enzymatic activity in the Ishikawa and ECC-1 cell lines. Furthermore, the effects of GnRH-(1-5) mediated by GPR101 and the subsequent increase in MMP-9 enzymatic activity lead to an increase in cellular invasion. These results suggest that GnRH-(1-5) and GPR101 regulation of MMP-9 may have physiological relevance in the metastatic potential of endometrial cancer cells.
['Cho-Clark|Madelaine|M|', 'Larco|Darwin O|DO|', 'Zahn|Brian R|BR|', 'Mani|Shaila K|SK|', 'Wu|T John|TJ|']
D045744:Cell Line, Tumor D002465:Cell Movement D016889:Endometrial Neoplasms D004815:Epidermal Growth Factor D005260:Female D015972:Gene Expression Regulation, Neoplastic D007987:Gonadotropin-Releasing Hormone D006801:Humans D020780:Matrix Metalloproteinase 9 D009362:Neoplasm Metastasis D010446:Peptide Fragments D010766:Phosphorylation D043562:Receptors, G-Protein-Coupled D015398:Signal Transduction
GnRH Endometrial Cancer Cell invasion Epidermal growth factor receptor (EGFR) G protein-coupled receptor (GPCR) Matrix metalloproteinase (MMP) Orphan receptor