Mechanism of gonadotropin-releasing hormone (GnRH)-I and -II-induced cell growth inhibition in ovarian cancer cells: role of the GnRH-I receptor and protein kinase C pathway.
In our previous studies, we demonstrated that ERK1/2 (extracellular signal-regulated protein kinase) and p38 MAPK (mitogen-activated protein kinase) are required for gonadotropin-releasing hormone (GnRH)-II-induced anti-proliferation of ovarian cancer cells. In the present study, we examined the role of the GnRH-I receptor, as well as the activation of protein kinase C (PKC), in the anti-proliferative effect induced by GnRH-I or II in ovarian cancer cells. Our results demonstrated that Antide, a GnRH-I antagonist, reversed the activation of ERK1/2 induced by GnRH-I or II and abolished the anti-proliferative effect of GnRH-I and II in ovarian cancer cells. Transfection of short-interfering RNA to abrogate the gene expression of the GnRH-I receptor reversed GnRH-I and II-induced anti-proliferation. These results indicate that GnRH-I or II induce anti-proliferation through the GnRH-I receptor in ovarian cancer cells. In addition, the activation of ERK1/2 by GnRH-I or II was mimicked by phorbol-12-myristate 13-acetate, a PKC activator. Pretreatment with GF109203X, an inhibitor of PKC, blocked GnRH-induced ERK1/2 activation and anti-proliferation. These results suggest that the activation of PKC is responsible for GnRH-induced ERK1/2 activation and anti-proliferation in ovarian cancer cells. Taken together, these results indicate that binding of GnRH-I and II to the GnRH-I receptor activates ERK1/2 through a PKC-dependent pathway and is essential for GnRH-induced anti-proliferation of ovarian cancer cells.
Kim
Ki-Yon
KY
Department of Obstetrics and Gynecology, British Columbia Children's and Women's Hospital, Child and Family Research Institute, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5.
Choi
Kyung-Chul
KC
Auersperg
Nelly
N
Leung
Peter C K
PC
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011493:Protein Kinase C / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; C484844:GNRHR protein, human; C427484:GNRHR2 protein, human; D007211:Indoles; D008301:Maleimides; D009842:Oligopeptides; D034741:RNA, Small Interfering; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; C047717:LHRH, His(5)-Trp(7)-Tyr(8)-; C057022:iturelix; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate