Type II Gonadotropin-Releasing Hormone Stimulates p38 Mitogen-Activated Protein Kinase and Apoptosis in Ovarian Cancer Cells

Recent results indicate that a novel second form of GnRH, GnRH-II, has an antiproliferative effect on ovarian and endometrial cancer cells and might be considered as a possible therapy for gynecological tumors. However, the mechanism of the GnRH-II-induced antiproliferative effect is not known. The p38 MAPK, one of the stress-activated protein kinases, is activated by diverse cellular stress and proinflammatory cytokines. In this study, the effect of GnRH-II on the activation of p38 MAPK was investigated, and its possible role in the regulation of cell proliferation and apoptosis was further examined in the human ovarian cancer cell line, OVCAR-3. Treatment with GnRH-II (100 nM) resulted in an activation of p38 MAPK in a time-dependent manner. A significant activation of p38 MAPK was observed at 2, 5, 10, and 15 min after GnRH-II treatment. The activation of p38 MAPK by GnRH-II was reversed in the presence of a specific inhibitor of p38 MAPK, SB203580 (1 microM). The transcription factor, activator protein-1, was activated (1.5-fold) by GnRH-II and attenuated in the presence of SB203580 (1 microM). Treatment with GnRH-II (1 nM, 100 nM, 10 microM) for 2, 4, and 6 d resulted in an inhibition of cell growth in OVCAR-3 cells as determined by thymidine incorporation assay. The effect of GnRH-II (100 nM) on cell proliferation was blocked by pretreatment with SB203580 (1 microM). Furthermore, a significant increase of apoptosis (1.6-fold) was observed after GnRH-II treatment, which was also reversed by pretreatment with SB203580 (1 microM). Taken together, these results indicate that p38 MAPK is involved in the GnRH-II-induced inhibition of cell growth through activator protein-1 activation, which may be related to induction of apoptosis in ovarian cancer cells.