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.
Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Madelaine
M
Cho-Clark
Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Darwin O
DO
Larco
Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Brian R
BR
Zahn
Departments of Molecular & Cellular Biology and Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Shaila K
SK
Mani
Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. Electronic address: twu@usuhs.edu.
T John
TJ
Wu
D045744:Cell Line, Tumor; D002465:Cell Movement; D016889:Endometrial Neoplasms / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C000594175:GPR101 protein, human; C495201:LHRH (1-5); D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D007987:Gonadotropin-Releasing Hormone; D004815:Epidermal Growth Factor; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
Cancer; Cell invasion; Endometrial; Epidermal growth factor receptor (EGFR); G protein-coupled receptor (GPCR); GnRH; Matrix metalloproteinase (MMP); Orphan receptor