Differential role of gonadotropin-releasing hormone on human ovarian epithelial cancer cell invasion

Abstract

Ovarian cancer is the most lethal of all gynecological cancers. Most deaths from ovarian cancer are due to widespread intraperitoneal metastases and malignant ascites. However, mechanisms of invasion in ovarian cancer remain poorly understood. In this study, we examined the effects of gonadotropin-releasing hormone (GnRH)-I (the classical mammalian GnRH), GnRH-II (a second form of GnRH), and GnRH receptor on invasion using two human ovarian carcinoma cell lines, OVCAR-3 and SKOV-3. Here we demonstrated that in OVCAR-3, GnRH-I and GnRH-II promoted cell invasion, whereas in SKOV-3, GnRH-I and GnRH-II inhibited cell invasion. Transfection of small interfering RNA to abrogate the gene expression of GnRH receptor reversed GnRH-I and GnRH-II-mediated invasion activities, suggesting that the same receptor, type I GnRH receptor, is essential for the effects of GnRH-I and GnRH-II in both OVCAR-3 and SKOV-3. Treatment of SKOV-3 cells with GnRH-I or GnRH-II resulted in a decrease in matrix metalloproteinase 2 but an increase in tissue inhibitor of metalloproteinase 2 secretions. In addition, we found that GnRH-I and GnRH-II interfered with activation of the phosphatidylinositol-3-kinase/AKT pathway that is well documented to stimulate proteolysis and invasion of ovarian cancer cells. Taken together, these observations suggest that GnRH-I and GnRH-II play key regulatory roles in ovarian tumor cell invasion and extracellular matrix degradation.

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

“…This difference in regulation suggests that high levels of GnRH receptor may enhance cellular response to GnRH stimulation, presumably because of more efficient signal amplification or altered signaling through coupling to different G proteins (Cheung and Wong, 2008). In support, we found that GnRH induces cell motility and invasive response selectively in Caov-3 and OVCAR-3, which express high levels of GnRH receptor (Cheung et al, 2006;Chen et al, 2007). In addition, GnRH has been shown to regulate its own synthesis, suggesting that GnRH may be involved in autocrine/ paracrine regulation (Kang et al, 2000).…”

“…(c) Cells were grown on glass coverslips and immunostained with anti-p120 ctn antibody and then detected with Texas red-conjugated secondary antibody. stimulate cell migration/invasion, high concentrations inhibit these functions (Cheung et al, 2006;Chen et al, 2007). The reasons are unknown, but the receptor expression level is known to be a determinant of different signal outcomes.…”

Stability, Permeability and Growth-Inhibitory Properties of Gonadotropin-Releasing Hormone Liposaccharides

“…GnRH isoforms and their synthetic relatives have been shown to have a dual action on GnRH receptor positive peripheral tissues (33). Low (nanomolar) concentrations of these peptides have exhibited a dose-dependent increase in cell proliferation, migration and invasion, yet concentrations over 100 nM have inhibited these functions (34). However, these actions may be inversed depending on the cell line and regardless of the tissue of origin.…”

“…However, these actions may be inversed depending on the cell line and regardless of the tissue of origin. In fact, it has been shown that GnRH can both induce and inhibit invasion of the human ovarian cancer cell lines, OVCAR-3 and SKOV-3, respectively (34). The mechanisms for these differences may be explained by the expression profiles of GnRH-R and their signal transduction.…”

New gonadotropin-releasing hormone glycolipids with direct antiproliferative activity and gonadotropin-releasing potency

“…GnRH receptor ligands have been shown to act differently on the GnRH receptor positive peripheral tissues at different doses (Mezo and Manea, 2010); a dose-dependent increase in cell proliferation at low (nanomolar) concentrations and inhibitory action at higher (micromolar) concentrations (Chen et al, 2007). This has been explained by the differential expression profiles of GnRH receptors (Mezo and Manea, 2010).…”