Gonadotropin-Releasing Hormone-II Increases Membrane Type I Metalloproteinase Production via β-Catenin Signaling in Ovarian Cancer Cells

• Published in: Endocrinology (Philadelphia) 2011-03, Vol.152 (3), p.764-772
• Main Authors: Ling Poon, Song, Lau, Man-Tat, Hammond, Geoffrey L, Leung, Peter C. K
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; beta Catenin - metabolism; Biological and medical sciences; Cancer; catenin; Cell Line, Tumor; Depletion; Female; Female genital diseases; Fundamental and applied biological sciences. Psychology; Gelatinase A; Gene Expression Regulation, Enzymologic - physiology; Gene Expression Regulation, Neoplastic - physiology; Glycogen; Glycogen synthase kinase 3; Glycogens; Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - metabolism; Gonadotropins; Gynecology. Andrology. Obstetrics; Humans; Invasiveness; Kinases; Lithium; Lithium chloride; Matrix metalloproteinase; Matrix Metalloproteinase 14 - genetics; Matrix Metalloproteinase 14 - metabolism; Matrix metalloproteinases; Medical sciences; Membranes; Metalloproteinase; Metastases; Nuclear transport; Nuclei (cytology); Ovarian cancer; Ovarian Neoplasms - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Pituitary (anterior); Pretreatment; Proenzymes; Proto-Oncogene Proteins c-akt - metabolism; Receptors; Receptors, LHRH - genetics; Receptors, LHRH - metabolism; Reporter gene; Signal Transduction; siRNA; Translocation; Tumor cell lines; Tumors; Up-Regulation; Vertebrates: endocrinology; β-Catenin
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-0942

GnRH-II/GnRHR activated PI3K/Akt pathway induces β-catenin signaling to up-regulate MT1-MMP synthesis in ovarian cancer cells. GnRH-II is produced by ovarian cancer cells and enhances their invasiveness in vitro. In our studies of OVCAR-3 and CaOV-3 ovarian cancer cell lines, GnRH-II treatment induced phosphorylation of Akt and glycogen synthase kinase (GSK)3β, as well as β-catenin accumulation in the nucleus, and the latter was reduced by small interfering RNA (siRNA)-mediated depletion of the GnRH receptor. The phosphatidylinositol 3 kinase (PI3K)/Akt pathway is involved in β-catenin-dependent signaling, and pretreatment of these human ovarian cancer cells with a PI3K/Akt inhibitor, LY294002, attenuated GnRH-II-stimulated phosphorylation of GSK3β and inhibited GnRH-II-induced invasion. It also attenuated GnRH-II induced trans-activation of a β-catenin-dependent reporter gene, most likely because GSK3β phosphorylation promotes translocation of β-catenin to the nucleus. Membrane type I matrix metalloproteinase (MT1-MMP) contributes to tumor progression directly, or by processing the latent MMP-2 zymogen, and is a known target of β-catenin signaling. When OVCAR-3 and CaOV-3 cells were treated with GnRH-II, MT1-MMP levels increased approximately 3-fold, whereas siRNA-mediated depletion of GnRH receptor or pretreatment with LY294002 abrogated this. In addition, lithium chloride, which increases GSK3β phosphorylation and the nuclear translocation of β-catenin, increased MT1-MMP levels in these ovarian cancer cells. By contrast, depletion of β-catenin by siRNA treatment abolished GnRH-II-induced MT1-MMP synthesis and reduced their invasive potential. Furthermore, siRNA-mediated reduction of MT1-MMP levels reduced GnRH-II-induced invasion in ovarian cancer cells. We therefore conclude that GnRH-II stimulates the PI3K/Akt pathway, and the phosphorylation of GSK3β, thereby enhancing the β-catenin-dependent up-regulation of MT1-MMP production, which contributes to ovarian cancer metastasis.