Human Type II GnRH Receptor Mediates Effects of GnRH on Cell Proliferation

Enomoto, Masahiro; Endo, Daisuke; Kawashima, Seiichiro; Park, Min Kyun

doi:10.2108/zsj.21.763

Cited by 25 publications

(19 citation statements)

References 58 publications

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“…However, our previously demonstrated data (8) suggest that in human endometrial and ovarian cancer cells, in addition to the GnRH-I receptor, another functional receptor may be present mediating the antiproliferative effects of the GnRH-I antagonist Cetrorelix and of GnRH-II agonist [D-Lys 6 ]-GnRH-II. These results are in accord with a report from Enomoto et al (9).…”

Section: Discussionsupporting

confidence: 94%

“…These findings suggested that the antiproliferative effects of the GnRH-I antagonist Cetrorelix and of GnRH-II are not mediated through the GnRH-I receptor. Our data are in agreement with a report from Enomoto et al (9) demonstrating that the human GnRH-II receptor is functional, and that its splice variant determines the direction of the cellular response to GnRH stimulation. Choi et al (10) have reported that the ligand (GnRH-II) is expressed in normal neoplastic ovarian surface epithelial cells and in cancers derived from these cells.…”

Section: Introductionsupporting

confidence: 94%

“…The effects of the GnRH-I agonist Triptorelin were abrogated after GnRH-I receptor knockout, whereas those of GnRH-II persisted (8), suggesting that the antiproliferative effects of GnRH-II are not mediated through the GnRH-I receptor. Enomoto et al (9) found that the splice variants of the human GnRH-II receptor determine the direction of the cellular response to GnRH stimulation. Choi et al (10) demonstrated the expression of the ligand (GnRH-II) in normal neoplastic ovarian surface epithelial cells and in cancers derived from these cells, suggesting the existence of an autocrine system based on GnRH-II in human cancers.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

GnRH-II receptor-like antigenicity in human placenta and in cancers of the human reproductive organs

Eicke¹,

Günthert²,

Viereck³

et al. 2005

eur j endocrinol

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We have recently demonstrated that the antiproliferative activity of GnRH-II on human endometrial and ovarian cancer cell lines is not mediated through the GnRH-I receptor. A functional receptor for human GnRH-II has not yet been identified. In this study, we have generated a polyclonal antiserum to the putative human GnRH-II receptor using a peptide (YSPTMLTEVPPC) corresponding to the third extracellular domain coupled to keyhole limpet haemocyanin via the Cys residue. A database search showed no identical peptide sequences in any other human gene. To avoid cross-reactions against two similar amino acid sequences the antiserum was pre-absorbed using these peptides. Immune histological sections of human placenta and human endometrial, ovarian and prostate cancers using rabbit anti-human GnRH-II receptor antiserum showed GnRH-II receptor-like staining. Western blot analysis of cell membrane preparations of human endometrial and ovarian cancer cell lines yielded a band at approximately 43 kDa whereas Western blot analysis of cell membrane preparations of ovaries obtained from the marmoset monkey (Callithrix jacchus) yielded a band at approximately 54 kDa. To identify the GnRH-II receptor-like antigen we used the photo-affinity labelling technique. ]-GnRH-II binding to its binding site. The GnRH-I antagonist Cetrorelix (10 27 M) showed a clearly stronger decrease, whereas GnRH-II agonist [D-Lys 6 ]-GnRH-II (10 27 M) was the most potent competitor. Western blot analysis of the same gel using rabbit anti-human GnRH-II receptor antiserum identified this band as GnRH-II receptor-like antigen.European Journal of Endocrinology 153 605-612

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Section: Discussionsupporting

confidence: 94%

Section: Introductionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

GnRH-II receptor-like antigenicity in human placenta and in cancers of the human reproductive organs

Eicke¹,

Günthert²,

Viereck³

et al. 2005

eur j endocrinol

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“…The antiproliferative effects of GnRH-II in human endometrial and ovarian cancer cells persist in cells after knockout of the GnRH-I-R, whereas the antiproliferative effect of GnRH-I agonist Triptorelin was completely abrogated in these cells, implying that the antiproliferative effects of GnRH-II are not mediated through the GnRH-I-R (25). Enomoto et al (39) confirmed effects of GnRH-II in HHUA, …”

Section: Discussionmentioning

confidence: 91%

Analogs of GnRH-I and GnRH-II inhibit epidermal growth factor-induced signal transduction and resensitize resistant human breast cancer cells to 4OH-tamoxifen

Günthert¹,

Gründker²,

Olota³

et al. 2005

eur j endocrinol

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About 50 -64% of human breast cancers express receptors for GnRH-I. Direct antiproliferative effects of analogs of GnRH-I on human breast cancer cell lines have been shown. They are at least in part mediated by antagonizing growth promoting effects of estradiol, epidermal growth factor (EGF) or insulin-like growth factor. Recently, expression of a putative receptor for GnRH-II in human tissues was demonstrated. Antiproliferative effects of GnRH-II in human endometrial and ovarian cancer cells were shown not to be mediated through the GnRH-I receptor. ]GnRH-II blocked EGF-induced autophosphorylation of EGF receptor and activation of mitogen-activated protein kinase (extracellular-signal-regulated kinase 1/2 (ERK1/2)) in these cells. In sublines of MCF-7 and T47D cells, which were developed to be resistant to 4OH-tamoxifen, HER-2/p185 was overexpressed. Pretreatment of these cell lines with Triptorelin or ]GnRH-II completely abolished resistance to 4OH-tamoxifen, assessed by 4OH-tamoxifen-induced apoptosis. Analogs of GnRH-I and GnRH-II counteract EGF-dependent signal transduction in human breast cancer cells with expression of receptors for GnRH-I and GnRH-II. Through this mechanism, they probably reverse acquired resistance to 4OH-tamoxifen mediated through overexpression or activation of receptors of the c-erbB family.European Journal of Endocrinology 153 613-625

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“…However, there is a discrepancy among the previous reports regarding the role of GnRH-I and II receptors. Enomoto et al (2004) showed that GnRH-II receptor is required to mediate the effect of GnRH-II, while Grundker et al (2004) reported that the anti-proliferative effect induced by GnRH-II is not mediated through GnRH-I receptor. On the other hand, a recent study demonstrated that transient transfection with GnRH-II receptor-reliquum inhibited the expression of GnRH-I receptor at the cell surface and impaired signaling via the GnRH-I receptor by reduction of GnRH-induced inositol phosphate accumulation, indicating that GnRH-I receptor may be a common receptor that mediates the effects of both GnRH-I and GnRH-II in ovarian cancer cell lines (Pawson et al 2005).…”

Section: Discussionmentioning

confidence: 99%

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

Kim

Choi²,

Auersperg³

et al. 2006

Endocr Relat Cancer

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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 antiproliferative 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 shortinterfering RNA to abrogate the gene expression of the GnRH-I receptor reversed GnRH-I and IIinduced 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 antiproliferation 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.

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Human Type II GnRH Receptor Mediates Effects of GnRH on Cell Proliferation

Cited by 25 publications

References 58 publications

GnRH-II receptor-like antigenicity in human placenta and in cancers of the human reproductive organs

GnRH-II receptor-like antigenicity in human placenta and in cancers of the human reproductive organs

Analogs of GnRH-I and GnRH-II inhibit epidermal growth factor-induced signal transduction and resensitize resistant human breast cancer cells to 4OH-tamoxifen

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

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