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Identification of signaling molecules involved in mediating the anti-proliferative effects of gonadotropin releasing hormone-I and -II on ovarian cancer cell lines Kim, Ki Yon

Abstract

In addition to its well-established role as a neuroendocrine regulator at the level of the pituitary gland, gonadotropin-releasing hormone (GnRH; GnRH-I) and a second form of GnRH have received consideration for therapeutic use in gynecological cancers. The objective of this thesis was to explore the signal transduction of GnRH-induced antiproliferative effects in ovarian cancer cells. It has been hypothesized that the action of GnRH-II may be mediated by the GnRH-I receptor, which is expressed in OVCAR-3 and SKOV-3 ovarian cancer cells. GnRH-I and II induced the activation of ERK1/2 and antiproliferative effect on on ovarian cancer cells and antide, a GnRH-I receptor antagonist, and transfection of short-interfering RNA (siRNA) of the GnRH-I receptor abolished GnRH-I and Il-induced anti-proliferation and extracellular signal-regulated protein kinase-1 and -2 (ERK1/2) phosphorylation. In addition, the GnRH-induced ERK1/2 activation was mimicked by phorbol-12-myristate 13-acetate, a protein kinase C (PKC) activator, and pretreatment with GF109203X, an inhibitor of PKC, blocked GnRH-induced ERK1/2 activation and anti-proliferation. There is accumulating evidence that activation of mitogenactivated protein kinases (MAPKs) by GnRH-I is important for cell proliferation, differentiation and apoptosis. In this study, the role of GnRH-II in activating MAPKs was investigated in ovarian cancer cells. ERK1/2 and p38 MAPK were activated following GnRH-II treatment. The activation of ERK1/2 by GnRH-II led to the phosphorylation of Elk-1, which was not blocked by PD98059, an inhibitor of MAPK/ERK kinase (MEK). In addition, the transcription factor, AP-1 was activated by GnRH-II and attenuated in the presence of SB203580, an inhibitor of p38 MAPK. Moreover, PD98059 and SB203580 reversed the GnRH-II-induced anti-proliferation. Treatments with GnRH-I or II resulted in the induction of apoptosis in ovarian cancer cells. Moreover, GnRH-induced apoptosis was blocked by SB203580, but not by PD98059. Treatment with genistein, a protein tyrosine kinase (PTK) inhibitor, reversed GnRH-induced anti-proliferation in ovarian cancer cells. In summary, having demonstrated the functional involvement of the signaling pathways described above in GnRH-I and Il-induced anti-proliferation and apoptosis, our studies support the hypothesis that GnRH-I and II elicit anti-proliferative effects in ovarian cancer cells via GnRH-I receptor, ERK1/2, p38, PKC and PTK.

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