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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epithelial ovarian carcinomas are the most common cause of death from gynecological malignancies and appear to arise from ovarian surface epithelium (OSE), but the exact mechanism of ovarian tumorigenesis has not been elucidated. Recent cloning of a second form of gonadotropin-releasing hormone (GnRH-II) has been reported in various human tissues including the ovary. However, the expression and role of GnRH-II in human OSE and ovarian carcinomas is not known. In the present study, we demonstrated that in addition to the GnRH receptor (GnRH-R), GnRH-II mRNA is expressed in normal OSE, immortalized OSE (IOSE) cells, primary cultures of ovarian tumors and ovarian cancer cell lines. Treatments with increasing doses (10(-9)-10(-7) M) of GnRH-I and -II resulted in a growth-inhibition in both non-tumorigenic IOSE-29 and tumorigenic IOSE-29EC cells. These results indicate for the first time the expression and potential anti-proliferative effect of GnRH-II, suggesting that GnRH-II, similar to GnRH-I, may have a growth-regulatory effect in normal and neoplastic OSE cells.
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PMID:Expression and antiproliferative effect of a second form of gonadotropin-releasing hormone in normal and neoplastic ovarian surface epithelial cells. 1160 May 88

Gonadotropin-releasing hormone (GnRH) analogues are used for the treatment of breast, prostate, and ovarian cancer. These analogues exert their antitumor effects indirectly by inhibiting the pituitary-gonadal axis, as well as by direct inhibition of proliferation of human breast cancer cells. However, the molecular mechanisms mediating these direct antiproliferative effects are not fully understood. We found that normal and malignant human breast tissue express two forms of the neuropeptide GnRH. Quantitative reverse transcription-PCR shows that mRNA encoding the GnRH-I and GnRH-II peptides are overexpressed in cancerous versus normal tissues obtained from the same patients. To elucidate the function of these peptides in breast cancer cells, we used the atlas human cDNA expression arrays technology and studied the differentially regulated genes after GnRH treatment of MCF-7 cells. We found that a wide range of GnRH-I or GnRH-II concentrations (0.1-10 nM) inhibit the expression of mRNA encoding the 60S acidic ribosomal phosphoproteins, P1 and P2. These results were confirmed by quantitative reverse transcription-PCR, as well as Western blot analysis and immunofluorescence staining. The P1 and P2 proteins interact with elongation factors EF1 and EF2, and the level of their phosphorylation is one of the regulatory mechanisms for the overall rate of protein elongation. Thus, reduced expression of P1 and P2 proteins can affect the rate of protein translation, thereby decreasing proliferation rate of cells. Our studies may therefore suggest a putative mechanism for the direct antiproliferative effect of GnRH in breast cancer cells.
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PMID:Two forms of gonadotropin-releasing hormone (GnRH) are expressed in human breast tissue and overexpressed in breast cancer: a putative mechanism for the antiproliferative effect of GnRH by down-regulation of acidic ribosomal phosphoproteins P1 and P2. 1186 79

Recently it was shown that a second GnRH system exists in primates. This study was conducted to investigate whether or not the receptor specific for GnRH type II is expressed in human endometrial and ovarian cancer cells and whether or not GnRH-II has effects on tumor cell proliferation. Expression of GnRH-II receptor mRNA in endometrial and ovarian cancer cell lines was demonstrated using RT-PCR and Southern blot analysis. The proliferation of these cell lines was dose- and time-dependently reduced by native GnRH-II. These effects were significantly more potent than the anitproliferative effects of equimolar doses of GnRH-I agonist Triptorelin (p<0.001). In the GnRH-II receptor positive but GnRH-I receptor negative ovarian cancer cell line SK-OV-3 native GnRH-II but not GnRH-I agonist Triptorelin had antiproliferative effects.
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PMID:Expression of gonadotropin-releasing hormone II (GnRH-II) receptor in human endometrial and ovarian cancer cells and effects of GnRH-II on tumor cell proliferation. 1188 21

Normal ovarian functions are regulated by a wide variety of endocrine hormones, local paracrine and autocrine factors, which functionally interact with each other in a highly coordinated fashion. Recent findings have demonstrated that both forms of gonadotropin-releasing hormone (GnRH-I and GnRH-II) are expressed in various compartments of the human ovary including the granulosa-luteal cells, ovarian surface epithelial cells and ovarian tumors, and their expressions have been shown to be tightly regulated by gonadal steroids and gonadotropins. Functionally, these neuropeptides exert diverse biological effects in the ovary via binding to their cognate receptors, supporting the notion that these peptides act as paracrine and autocrine factors in modulating local ovarian functions. In this review, we will summarize recent literatures regarding the regulation of GnRH-I and GnRH-II gene expressions in the human ovary, and discuss the possible signal transduction mechanisms by which these hormones exert their actions in the gonad. Recent cloning of the second form of the GnRH receptor (GnRH-II receptor) in primates and other vertebrates demonstrated that it was structurally, and thus, functionally distinct from the GnRH-I receptor. Cell proliferation studies showed that GnRH-II inhibited the growth of human ovarian cancer cells that express GnRH-II but not GnRH-I receptor, indicating that the GnRH-II binding sites are functional in these cells. However, it remains unknown if GnRH-II receptor is expressed as a full-length, properly processed and functional gene transcript in humans, and its potential physiological roles such as differential regulation of gonadotropin secretion, neuroendocrine modulation and female sexual behavior await further investigation.
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PMID:Multi-factorial role of GnRH-I and GnRH-II in the human ovary. 1277 Jul 44

Gonadotrophin-releasing hormone (GnRH) functions as a key neuroendocrine regulator of the hypothalamic-pituitary-gonadal axis. In addition to the hypothalamus and pituitary gland, GnRH and its receptor have been detected in other reproductive tissues including the gonads, placenta and tumours arising from these tissues. Recently, a second form of GnRH (GnRH-II) and type II GnRH receptor have been found in normal ovarian surface epithelium and neoplastic counterparts. The two types of GnRH may play an important role as an autocrine/paracrine regulator of reproductive functions and ovarian tumour growth. In this review, the distribution and potential roles of GnRH-I/-II and their GnRH receptors in the ovarian cells and ovarian cancer will be discussed.
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PMID:Potential role of gonadotrophin-releasing hormone (GnRH)-I and GnRH-II in the ovary and ovarian cancer. 1279 Jul 79

Recent results indicate that a novel second form of GnRH, GnRH-II, has an antiproliferative effect on ovarian and endometrial cancer cells and might be considered as a possible therapy for gynecological tumors. However, the mechanism of the GnRH-II-induced antiproliferative effect is not known. The p38 MAPK, one of the stress-activated protein kinases, is activated by diverse cellular stress and proinflammatory cytokines. In this study, the effect of GnRH-II on the activation of p38 MAPK was investigated, and its possible role in the regulation of cell proliferation and apoptosis was further examined in the human ovarian cancer cell line, OVCAR-3. Treatment with GnRH-II (100 nM) resulted in an activation of p38 MAPK in a time-dependent manner. A significant activation of p38 MAPK was observed at 2, 5, 10, and 15 min after GnRH-II treatment. The activation of p38 MAPK by GnRH-II was reversed in the presence of a specific inhibitor of p38 MAPK, SB203580 (1 microM). The transcription factor, activator protein-1, was activated (1.5-fold) by GnRH-II and attenuated in the presence of SB203580 (1 microM). Treatment with GnRH-II (1 nM, 100 nM, 10 microM) for 2, 4, and 6 d resulted in an inhibition of cell growth in OVCAR-3 cells as determined by thymidine incorporation assay. The effect of GnRH-II (100 nM) on cell proliferation was blocked by pretreatment with SB203580 (1 microM). Furthermore, a significant increase of apoptosis (1.6-fold) was observed after GnRH-II treatment, which was also reversed by pretreatment with SB203580 (1 microM). Taken together, these results indicate that p38 MAPK is involved in the GnRH-II-induced inhibition of cell growth through activator protein-1 activation, which may be related to induction of apoptosis in ovarian cancer cells.
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PMID:Type II gonadotropin-releasing hormone stimulates p38 mitogen-activated protein kinase and apoptosis in ovarian cancer cells. 1518 Oct 93

Although a novel second form of GnRH (GnRH-II) has been reported to have an antiproliferative effect on gynecologic cancer cells, its biological mechanism remains to be elucidated. We have previously demonstrated that GnRH-II activates p38 MAPK. There is accumulating evidence that activation of MAPKs by GnRH-I and -II is important for cell proliferation, differentiation, and apoptosis. In the present study, we further investigated the involvement of GnRH-II in the inhibition of cell proliferation and activation of ERK1/2 and c-Jun N-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) in ovarian cancer cells, OVCAR-3. The [(3)H]thymidine incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays revealed that treatment with GnRH-II suppresses cell proliferation of ovarian cancer cells. Western blot analysis demonstrated that ERK1/2 was activated by GnRH-II (100 nm). Moreover, PD98059 (10 mum), an inhibitor of a MAPK/ERK kinase, reversed the activation of ERK1/2 induced by GnRH-II. The activation of ERK1/2 by GnRH-II subsequently phosphorylated Elk-1 as a downstream pathway, which was blocked by PD98059. On the other hand, it is not likely that GnRH-II activates the JNK/SAPK pathway. Taken together, these results indicate that the ERK1/2 pathway is involved in the effect of GnRH-II on antiproliferation and may be an important target for ovarian cancer therapy.
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PMID:Extracellular signal-regulated protein kinase, but not c-Jun N-terminal kinase, is activated by type II gonadotropin-releasing hormone involved in the inhibition of ovarian cancer cell proliferation. 1559 81

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. Photochemical reaction of (125)I-labelled (4-azidobenzoyl)-N-hydroxysuccinimide-[d-Lys(6)]-GnRH-II (10(-9) M) with cell membrane preparations of human endometrial and ovarian cancer cells yielded a band at approximately 43 kDa. In competition experiments, the GnRH-I agonist Triptorelin (10(-7) M) showed a weak decrease of (125)I-labelled (4-azidobenzoyl)-N-hydroxysuccinimide-[d-Lys(6)]-GnRH-II binding to its binding site. The GnRH-I antagonist Cetrorelix (10(-7) M) showed a clearly stronger decrease, whereas GnRH-II agonist [d-Lys(6)]-GnRH-II (10(-7) 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.
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PMID:GnRH-II receptor-like antigenicity in human placenta and in cancers of the human reproductive organs. 1618 82

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. Now we demonstrate direct anti-proliferative effects of the GnRH-I analog Triptorelin and the GnRH-II analog [d-Lys(6)]GnRH-II in MCF-7 and T47D human breast cancer cells expressing GnRH-I receptors and putative GnRH-II receptors. Pretreatment with Triptorelin or [d-Lys(6)]GnRH-II blocked EGF-induced autophosphoryla-tion 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 [d-Lys(6)]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.
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PMID:Analogs of GnRH-I and GnRH-II inhibit epidermal growth factor-induced signal transduction and resensitize resistant human breast cancer cells to 4OH-tamoxifen. 1618 83

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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PMID:Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid by gonadotropins in human immortalized ovarian surface epithelium and ovarian cancer cells. 1672 89


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