Gonadotropin-releasing hormone-II increases membrane type I metalloproteinase production via beta-catenin signaling 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.
Department of Obstetrics and Gynaecology, University of British Columbia, Room 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5.
Song
S
Ling Poon
Man-Tat
MT
Lau
Geoffrey L
GL
Hammond
Peter C K
PC
Leung
D045744:Cell Line, Tumor; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*
D011966:Receptors, LHRH; D051176:beta Catenin; D007987:Gonadotropin-Releasing Hormone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053511:Matrix Metalloproteinase 14