GnRH enhances matrix metalloproteinases-dependent invasion of human ovarian cancer cells

Abstract

Objectives: To investigate the contribution of GnRH in the invasive behavior of human ovarian cancer cells and to unveil the mechanism underlying this process. Methods: In vitro migration and cell invasion assays were performed with two human ovarian cancer cell lines CaOV-3 and OVCAR-3 in the presence of GnRH agonist. RT-PCR, Western blot, and gelatin zymography were used to investigate the effect of GnRH on metastasis-related proteinases, matrix metalloproteinase (MMP)-2 and MMP-9. The signaling pathway involved was identified by using specific small molecule inhibitors and dominant negative mutants. Results: The in vitro assays revealed a biphasic nature of GnRH; low concentrations of GnRH agonist increased cell motility and invasiveness of CaOV-3 and OVCAR-3, but the stimulatory effect was insignificant at higher concentrations. Moreover, we demonstrated that expression and activation of MMP-2 and MMP-9 were functionally related to GnRH-mediated invasion, and this was through the c-Jun N-terminal kinase signaling pathway. Conclusion: These results suggest a novel role of GnRH signaling cascade in the invasive phenotype and motility of human ovarian cancer cells.