Gi protein activation of gonadotropin-releasing hormone–mediated protein dephosphorylation in human endometrial carcinoma

Imai, Atsushi; Horibe, Shinji; Takagi, Atsushi; Tamaya, Teruhiko

doi:10.1016/s0002-9378(97)70501-5

Cited by 46 publications

(26 citation statements)

References 20 publications

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“…Although type I GnRHR transcripts detected in breast and ovarian cancers are identical to those of the pituitary, the receptors may differ functionally (Eidne et al 1987, Kakar et al 1994, Imai et al 1997, Emons et al 1998, Schally & Nagy 1999, Cheng & Leung 2005. Pituitary GnRHRs have high affinity for agonists such as Buserelin, whereas the vast majority of GnRHRs in extra-pituitary sites are low affinity and there are also apparent differences in signaling.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to expression in the pituitary, GnRH receptors (GnRHRs) are found (often along with GnRH) in many cancers of reproductive tissues (Cheng & Leung 2005). Interest in these extra-pituitary GnRHRs stems primarily from the fact that GnRH analogs (or their cytotoxic derivatives) can inhibit proliferation of cell lines derived from such cancers, and that direct anti-proliferative effects may therefore contribute to the therapeutic effects of GnRH analogs in cancer treatment (Eidne et al 1987, Kakar et al 1994, Imai et al 1997, Emons et al 1998, Schally & Nagy 1999, Cheng & Leung 2005.…”

Section: Introductionmentioning

confidence: 99%

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Intracellular gonadotropin-releasing hormone receptors in breast cancer and gonadotrope lineage cells

Sedgley¹,

Finch²,

Caunt³

et al. 2006

Journal of Endocrinology

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Gonadotropin-releasing hormone receptors (GnRHRs) are expressed in gonadotropes and several extra-pituitary sites. They are assumed to be cell surface proteins but the human (h) GnRHR lacks features favoring plasma membrane localization and receptor location varies with cell type. When expressed in mammary (MCF7) cells, cell surface hGnRHR binding was much lower than that of mouse and sheep GnRHRs (type I GnRHRs without C-terminal tails), Xenopus (X) and marmoset type II GnRHRs (type II GnRHRs with C-tails) or chimeric receptors (type I GnRHRs with added XGnRHR C-tails). hGnRHR binding was higher in aT4 (gonadotrope-derived) cells and was increased less by C-tail addition. Whole cell levels of tagged human, Xenopus and chimeric GnRHRs were comparable (Western blotting) and confocal microscopy revealed that the hGnRHR is primarily intracellular (distribution similar to the endoplasmic reticulum marker, calreticulin), whereas most XGnRHR is at the plasma membrane, and adding the C-tail increased cell surface hGnRHR levels. A membrane-permeant antagonist increased cell surface hGnRHR number (O4-fold, t 1 ⁄ 2 Z 4 h) and also increased hGnRHR signaling and hGnRHRmediated inhibition of proliferation. A more rapid increase in hGnRHR binding occurred when the temperature was raised from 4 to 37 8C (O5-fold, t 1 ⁄ 2 Z15 min) and this effect was prevented by mutation to prevent signaling. Thus, cell surface GnRHR expression depends on receptor and cell type and the hGnRHR is primarily an intracellular protein that traffics to the cell surface for signaling in MCF7 cells. Manipulations favoring such trafficking may facilitate selective targeting of extra-pituitary GnRHRs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intracellular gonadotropin-releasing hormone receptors in breast cancer and gonadotrope lineage cells

Sedgley¹,

Finch²,

Caunt³

et al. 2006

Journal of Endocrinology

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“…The different effects of GnRHa on different kinds of cells may be due to two reasons. First, GnRH receptor is coupled to pertussis toxin-sensitive guanosine triphosphate (GTP)-binding proteins of the Gi family in reproductive tract tumors (29,30). Recent studies have identified that members of the pertussis toxin-insensitive GTP-binding proteins of the Gq/G11 subfamily mediate the message from GnRH receptor in pituitary gonadotrophs (31,32).…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of proliferation and up-regulation of apoptosis by gonadotropin-releasing hormone agonist in cultured uterine leiomyoma cells

Wang

Matsuo

Kurachi

et al. 2002

European Journal of Endocrinology

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Objective: To elucidate the direct effects of gonadotropin-releasing hormone agonist (GnRHa) on the growth of human uterine leiomyoma cells, cell proliferation and apoptosis in cultured leiomyoma cells treated with GnRHa were investigated. Methods: Isolated leiomyoma cells were subcultured in DMEM supplemented with 10% FBS for 5 days and stepped down to serum-free conditions for an additional 6 days in the presence or absence of graded concentrations of GnRHa (10 29 mol/l to 10 212 mol/l). The effects of GnRHa on the number of viable cells, expression of proliferating cell nuclear antigen (PCNA), Fas and Fas ligand, and apoptosis in cultured leiomyoma cells were examined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide) assay, immunocytochemical analysis, Western blot analysis and TUNEL assay respectively. RT-PCR was performed to detect the expression of GnRH receptor mRNA in cultured leiomyoma cells. Results: Treatment with GnRHa resulted in a decrease in the number of cultured viable leiomyoma cells assessed by MTT assay in a dose-dependent manner compared with that in control cultures ðP , 0:01Þ: The growth inhibition of cultured leiomyoma cells treated with GnRHa in concentrations higher than 10 210 mol/l was associated with the suppression of the proliferative potential characterized by a decrease in PCNA-positive rate of the cultured cells ðP , 0:01Þ and an increase in the apoptosis-positive rate assessed by TUNEL assay ðP , 0:05 and P , 0:01Þ: GnRHa markedly increased the expression of Fas and induced the expression of Fas ligand in the cultured leiomyoma cells on the basis of Western blot analysis. These direct effects of GnRHa on the number of viable cultured leiomyoma cells, PCNA-positive rate, apoptosis-positive rate and Fas/Fas ligand expression in the cultured leiomyoma cells were only attained after the 4-day treatment. RT-PCR analysis revealed that GnRH receptor mRNA was expressed in cultured leiomyoma cells. Conclusions:The present results demonstrate that GnRHa directly inhibits the growth of human uterine leiomyoma cells by suppressing cell proliferation and inducing apoptosis, which might be associated with the increase in Fas expression and the induction of Fas ligand expression in the cells.

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“…GnRH and GnRH-Rs are also found in many gonadal steroid-dependent cancers, including those of the breast, endometrium, prostate and ovary (Eidne et al 1985, Miller et al 1985, Emons et al 1993, 1998, Emons & Schally 1994, Imai et al 1997, Limonta et al 1999, 2001, Schally 1999, Schally & Nagy 1999, Imai & Tamaya 2000, Grundker et al 2001. Interest in these receptors stems primarily from the fact that GnRH analogues and cytotoxic derivatives of GnRH analogues can inhibit proliferation of cancer-derived cell lines, suggesting that such direct effects may contribute to the beneficial effects of GnRH analogues in cancer therapy.…”

Section: Gnrh-rs In Hormone-dependent Cancersmentioning

confidence: 99%

Signalling, cycling and desensitisation of gonadotrophin-releasing hormone receptors

McArdle¹,

Franklin²,

Green³

et al. 2002

Journal of Endocrinology

160

103

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Sustained stimulation of G-protein-coupled receptors (GPCRs) typically causes receptor desensitisation, which is mediated by phosphorylation, often within the C-terminal tail of the receptor. The consequent binding of -arrestin not only prevents the receptor from activating its G protein (causing desensitisation), but can also target it for internalisation via clathrin-coated vesicles and can mediate signalling to proteins regulating endocytosis and mitogenactivated protein kinase (MAPK) cascades. GnRH acts via phospholipase C (PLC)-coupled GPCRs on pituitary gonadotrophs to stimulate a Ca 2+ -mediated increase in gonadotrophin secretion. The type I GnRH receptors (GnRH-Rs), found only in mammals, are unique in that they lack C-terminal tails and apparently do not undergo agonist-induced phosphorylation or bind -arrestin; they are therefore resistant to receptor desensitisation and internalise slowly. In contrast, the type II GnRH-Rs, found in numerous vertebrates, possess such tails and show rapid desensitisation and internalisation, with concomitant receptor phosphorylation (within the C-terminal tails) or binding of -arrestin, or both. The association with -arrestin may also be important for regulation of dynamin, a GTPase that controls separation of endosomes from the plasma membrane. Using recombinant adenovirus to express GnRH-Rs in Hela cells conditionally expressing a dominant negative mutant of dynamin (K44A), we have found that blockade of dynamindependent endocytosis inhibits internalisation of type II (xenopus) GnRH-Rs but not type I (human) GnRH-Rs. In these cells, blockade of dynamin-dependent internalisation also inhibited GnRH-R-mediated MAPK activation, but this effect was not receptor specific and therefore not dependent upon dynamin-regulated GnRH-R internalisation. Although type I GnRH-Rs do not desensitise, sustained activation of GnRH-Rs causes desensitisation of gonadotrophin secretion, and we have found that GnRH can cause down-regulation of inositol (1,4,5) trisphosphate receptors and desensitisation of Ca 2+ mobilisation in pituitary cells. The atypical resistance of the GnRH-R to desensitisation may underlie its atypical efficiency at provoking this downstream adaptive response. GnRH-Rs are also expressed in several extrapituitary sites, and these may mediate direct inhibition of proliferation of hormone-dependent cancer cells. Infection with type I GnRH-R-expressing adenovirus facilitated expression of high-affinity, PLC-coupled GnRH-R in mammary and prostate cancer cells, and these mediated pronounced antiproliferative effects of receptor agonists. No such effect was seen in cells transfected with a type II GnRH-R, implying that it is mediated most efficiently by a nondesensitising receptor. Thus it appears that the mammalian GnRH-Rs have undergone a period of rapidly accelerated molecular evolution that is of functional relevance to GnRH-Rs in pituitary and extrapituitary sites.

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Gi protein activation of gonadotropin-releasing hormone–mediated protein dephosphorylation in human endometrial carcinoma

Cited by 46 publications

References 20 publications

Intracellular gonadotropin-releasing hormone receptors in breast cancer and gonadotrope lineage cells

Intracellular gonadotropin-releasing hormone receptors in breast cancer and gonadotrope lineage cells

Down-regulation of proliferation and up-regulation of apoptosis by gonadotropin-releasing hormone agonist in cultured uterine leiomyoma cells

Signalling, cycling and desensitisation of gonadotrophin-releasing hormone receptors

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