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Jung-Hye Choi Department of Obstetrics and Gynecology, British Columbia Children’s and Women’s Hospital, British Columbia Research Institute for Children’s and Women’s Health, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5

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Kyung-Chul Choi Department of Obstetrics and Gynecology, British Columbia Children’s and Women’s Hospital, British Columbia Research Institute for Children’s and Women’s Health, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5

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Nelly Auersperg Department of Obstetrics and Gynecology, British Columbia Children’s and Women’s Hospital, British Columbia Research Institute for Children’s and Women’s Health, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5

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Peter C K Leung Department of Obstetrics and Gynecology, British Columbia Children’s and Women’s Hospital, British Columbia Research Institute for Children’s and Women’s Health, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5

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Gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) have been implicated as probable risk factors in epithelial ovarian carcinomas, most of which are derived from ovarian surface epithelium (OSE). Since epidermal growth factor (EGF) increases the growth of ovarian surface epithelial cells, we determined the effect of gonadotropins on the expression of epidermal growth factor receptor (EGFR). We investigated the basal levels of EGFR mRNA and protein, and the mechanisms involved in the regulation of EGFR at the transcriptional and translational levels by FSH and LH. The immortalized OSE cell lines (IOSE) derived from normal OSE cells by transfecting SV40 T-antigen (IOSE-80 and IOSE-80PC, a post-crisis line) and ovarian cancer cell lines were employed. A significantly lower level of EGFR was observed in both IOSE-80 and IOSE-80PC cells when compared with the ovarian cancer cell lines, OVCAR-3 and SKOV-3. Treatment of IOSE-80PC cells with FSH and LH (10−7 and 10−6 g/ml) resulted in a significant increase in EGFR mRNA at 24 h and EGFR protein at 48 h, whereas the treatment with gonadotropins for 24–48 h induced a mild increase in EGFR in OVCAR-3, but not in SKOV-3 cells. In addition, IOSE-80PC cells treated with gonadotropins and EGF (10 nM) exhibited an additive stimulation of mitogenesis. Further, FSH and LH significantly increased activities of various kinases at 5–10 min, and pre-treatments with LY294002 (an inhibitor of PI3K) or PD98059 (an inhibitor of ERK1/2) partially blocked the gonadotropin-induced up-regulation of EGFR in IOSE-80PC cells. We investigated whether the effect of gonadotropins on EGFR mRNA levels is induced by increased transcription and/or by altered mRNA stability. Treatment of IOSE-80PC cells with FSH (10−7 and 10−6 g/ml) significantly enhanced the activity of the EGFR promoter (120 and 140% increase, respectively) at 24 h, and treatment with LH (10−7 g/ml) for 24 h induced an increase in the activity of EGFR promoter (30%) in these cells. On the other hand, LH resulted in a significant increase in EGFR mRNA stability in the decay curves. Taken together, these results suggest that the effect of gonadotropins on the expression of EGFR may affect cell growth via ERK-1/-2 and PI3K pathways in pre-neoplastic ovarian surface epithelial cells, and that FSH and LH increase EGFR mRNA by different mechanisms. The former increased EGFR gene transcription essentially, whereas the latter mainly enhanced EGFR mRNA stability.

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Jung-Hye Choi 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 St, Vancouver, British Columbia, Canada, V6H 3V5

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Kyung-Chul Choi 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 St, Vancouver, British Columbia, Canada, V6H 3V5

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Nelly Auersperg 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 St, Vancouver, British Columbia, Canada, V6H 3V5

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Peter C K Leung 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 St, Vancouver, British Columbia, Canada, V6H 3V5

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Although gonadotropin-releasing hormone (GnRH) has been shown to play a role as an autocrine/ paracrine regulator of cell growth in ovarian surface epithelium and ovarian cancer, the factors which regulate the expression of GnRH and its receptor in these cells are not well characterized. In the present study, we employed real-time PCR to determine the potential regulatory effect of gonadotropins on the expression levels of GnRH I (the mammalian GnRH), GnRH II (a second form of GnRH) and their common receptor (GnRHR) in immortalized ovarian surface epithelial (IOSE-80 and IOSE-80PC) cells and ovarian cancer cell lines (A2780, BG-1, CaOV-3, OVCAR-3 and SKOV-3). The cells were treated with increasing concentrations (100 and 1000 ng/ml) of recombinant follicle-stimulating hormone (FSH) or luteinizing hormone (LH) for 24 h. Treatment with FSH or LH reduced GnRH II mRNA levels in both IOSE cell lines and in three out of five ovarian cancer cell lines (A2780, BG-1 and OVCAR-3). A significant decrease in GnRHR mRNA levels was observed in IOSE and ovarian cancer cells, except CaOV-3 cells, following treatment with FSH or LH. In contrast, treatment with either FSH or LH had no effect on GnRH I mRNA levels in these cells, suggesting that gonadotropins regulate the two forms of GnRH and its receptor differentially. In separate experiments, the effect of gonadotropins on the anti-proliferative action of GnRH I and GnRH II agonists in IOSE-80, OVCAR-3 and SKOV-3 cells was investigated. The cells were pretreated with FSH or LH (100 ng/ml) for 24 h after which they were treated with either GnRH I or GnRH II (100 ng/ml) for 2 days, and cell growth was assessed by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide] assay. Pretreatment of the cells with FSH or LH significantly reversed the growth inhibitory effect of GnRH I and GnRH II agonists in these cell types. These results provide the first demonstration of a potential interaction between gonadotropins and the GnRH system in the growth regulation of normal ovarian surface epithelium and its neoplastic counterparts.

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Jung-Hye Choi Department of Obstetrics and Gynecology, Graduate Institute of Clinical Medical Sciences, Center for Traditional Chinese Medicine, Department of Obstetrics and Gynecology, Department of Oriental Pharmacy, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5
Department of Obstetrics and Gynecology, Graduate Institute of Clinical Medical Sciences, Center for Traditional Chinese Medicine, Department of Obstetrics and Gynecology, Department of Oriental Pharmacy, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5

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Chien-Lin Chen Department of Obstetrics and Gynecology, Graduate Institute of Clinical Medical Sciences, Center for Traditional Chinese Medicine, Department of Obstetrics and Gynecology, Department of Oriental Pharmacy, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5
Department of Obstetrics and Gynecology, Graduate Institute of Clinical Medical Sciences, Center for Traditional Chinese Medicine, Department of Obstetrics and Gynecology, Department of Oriental Pharmacy, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5

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Song Ling Poon Department of Obstetrics and Gynecology, Graduate Institute of Clinical Medical Sciences, Center for Traditional Chinese Medicine, Department of Obstetrics and Gynecology, Department of Oriental Pharmacy, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5

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Hsin-Shih Wang Department of Obstetrics and Gynecology, Graduate Institute of Clinical Medical Sciences, Center for Traditional Chinese Medicine, Department of Obstetrics and Gynecology, Department of Oriental Pharmacy, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5
Department of Obstetrics and Gynecology, Graduate Institute of Clinical Medical Sciences, Center for Traditional Chinese Medicine, Department of Obstetrics and Gynecology, Department of Oriental Pharmacy, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5

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Peter C K Leung Department of Obstetrics and Gynecology, Graduate Institute of Clinical Medical Sciences, Center for Traditional Chinese Medicine, Department of Obstetrics and Gynecology, Department of Oriental Pharmacy, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5

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In addition to their critical roles in folliculogenesis and ovarian granulosa cell steroidogenesis, gonadotropins have been implicated as potential risk factors in ovarian epithelial carcinomas, most of which are derived from ovarian surface epithelium (OSE). However, the molecular mechanism underlying the effects of FSH and LH in OSE and its neoplastic counterpart is not well understood. We previously demonstrated that gonadotropins promote the growth of OSE cells by regulating the levels of epidermal growth factor receptor (EGFR) via the activation of ERK1/2 and PI3K pathways in immortalized human OSE (IOSE) cells. In this study, we investigated whether cAMP and its novel binding target, named exchange protein activated by cAMP (Epac), are involved in the gonadotropin-induced EGFR expression in OSE cells. Gonadotropins elevated intracellular cAMP levels in both IOSE and granulosa cells, and this increase was attenuated by SQ22536, an inhibitor of adenylyl cyclase (AC). The activation of the ERK1/2 and Akt pathways as well as the expression of EGFR was stimulated by reagents that elevate intracellular cAMP levels, via cAMP analog 8-bromo-cAMP and AC activator forskolin. A similar increase was observed when the cells were treated with a novel cAMP analog, 8-(4-chlorophenylthio)-2′-O-methyl adenosine-3′,5′-cyclic monophosphate (8-CPT-2ME-cAMP), which activates Epac specifically but not PKA. Moreover, the gonadotropin-induced EGFR expression and ERK1/2 and Akt activation were abolished by overexpression of dominant negative Epac. Taken together, these results indicate that the AC/cAMP/Epac signaling pathway may mediate the up-regulation of EGFR by gonadotropins via ERK1/2 and Akt activation.

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