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

Gonadotropin-releasing hormone (Gn-RH) analogs inhibit ovarian cancer cell proliferation in vivo and in vitro. To examine whether Gn-RH receptor (Gn-RHR) mediates direct antiproliferative effects, we attempted to determine inhibitory regulation by Gn-RH of phosphatidylinositol (PtdIns) kinase activity, known to stimulate mitogenic response, in plasma membranes isolated from ovarian carcinoma samples. Ovarian carcinomas surgically removed and cloned cell line SK-OV3 had been screened for Gn-RHR expression prior to plasma membrane isolation. PtdIns kinase activity was measured as phosphorylation of exogenous substrate PtdIns by the purified plasma membranes. Incubation of the plasma membranes isolated from Gn-RHR-positive specimens with [gamma-32P]ATP and PtdIns caused [32P]phosphate incorporation into PtdIns phosphate (PtdInsP) in a time-dependent manner. Concomitant exposure of the membrane preparations to Gn-RH analog buserelin (1 microM) led to a 70% inhibition of the PtdInsP production, when compared to control. After 10 or 15 min of an initial incubation, the addition of analog resulted in similar suppression of PtdIns phosphorylation. This inhibition was dependent on the buserelin dose, and a half-maximal effect occurred at a concentration 0.1 to 1 nM of buserelin. Degradation of the produced PtdInsP in the plasma membranes was not affected by the Gn-RH analog. Similar inhibition of PtdIns kinase activities was observed in membranes prepared from cells that had been pretreated with buserelin (1 microM) for 48 hr prior to assay. These findings demonstrate that PtdIns kinase activity is suppressed by Gn-RH analog in plasma membrane isolated from GnRHR-expressing ovarian carcinomas, suggesting a tight coupling of Gn-RHR to PtdIns. The inhibition of membrane-associated PtdIns kinase by Gn-RHR occupancy may mediate the antimitogenic action of the hormone on human ovarian carcinomas.
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PMID:Evidence for tight coupling of gonadotropin-releasing hormone receptors to phosphatidylinositol kinase in plasma membrane from ovarian carcinomas. 778 76

A polyclonal antiserum was generated in ovariectomized sheep against a synthetic peptide corresponding to amino acids 5-17 of the deduced mouse pituitary gonadotropin-releasing hormone (GnRH) receptor. Antipeptide antibodies did not bind native cells, but did react strongly with a human ovarian cancer cell line (OVCAR-3) reportedly sensitive to GnRH. Growth of cultured OVCAR-3 cells was specifically suppressed by antipeptide serum. This was attributed in part to programmed death (chromatin condensation and DNA fragmentation) of cells by antibody-induced apoptosis. Antibodies also exhibited a cytolytic effect (lactate dehydrogenase release) toward OVCAR-3 cells in the presence of the complement. Endometria of passively immunized mice lacked development; thus, antipeptide antibodies evidently recognize Mullerian duct derivatives. Experiments are in progress to determine whether the putative antigen is a variant of the pituitary GnRH receptor or a largely dissimilar protein. Effector-functional antibodies could be useful in the management of ovarian or uterine neoplasia.
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PMID:Induction of apoptotic or lytic death in an ovarian adenocarcinoma cell line by antibodies generated against a synthetic N-terminal extracellular domain gonadotropin-releasing hormone receptor peptide. 801 35

The presence of gonadotropin-releasing hormone (GnRH) binding sites in biopsy samples of human epithelial ovarian cancer and ovarian tumor cell lines as well as the demonstration of the inhibitory effects of GnRH analogues on the growth of these cells raised the possibility that GnRH is produced locally by ovarian cancer cells. In order to investigate an autocrine/paracrine regulatory mechanism in human carcinomas, we have studied the expression of GnRH and GnRHR mRNA in human ovarian epithelial cell lines (OVCAR-3 and SKOV-3), human choriocarcinoma cell line (JEG-3) and human hepatocarcinoma cell line (HepG 2). Using primers corresponding to published human GnRH and GnRHR cDNA sequences, predicted PCR products were obtained from these cell lines by reverse transcription-polymerase chain reaction (RT-PCR) and confirmed by Southern hybridization. Sequencing analysis of GnRH PCR products showed that their sequences have 100% identity to the published human GnRH cDNA sequence. These results indicated that GnRH and GnRHR genes are expressed in all the cell lines tested in the present study, and strengthen the concept that GnRH may act as an autocrine regulator on the growth of cancer cells.
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PMID:Expression of the messenger RNA for gonadotropin-releasing hormone and its receptor in human cancer cell lines. 962

Six endometrial cancer cell lines (Ishikawa, EIIL, HEC1A, 6, 50 and 59), one breast cancer cell line (MCF-7) and two ovarian cancer cell lines (OVHS-1, HRA) were treated for 24 or 168 h with a gonadotropin-releasing hormone (GnRH) analogue, Buserelin acetate, and the cellular growth profile was studied. All these cell lines except for the HRA line had positive GnRH receptor mRNA expression detected by reverse transcriptase polymerase chain reaction. GnRHa suppressed cell growth after 168 h of exposure, but not after 24 h. Suppression of cell growth by the exposure to cis-platinum (CDDP, 10 nM for 24 h) was significantly increased in the presence of GnRHa for 168 h. The mechanism of this growth inhibition was tested by examining both RNA components of human telomerase (hTR) expression and telomerase activity. The results showed that GnRHa inhibits telomerase activity without altering the RNA component of telomerase expression. The present data suggest that GnRH analogue may modulate endometrial, breast and ovarian cancer cell growth through modifying the telomerase activity. Since GnRHa increased the cytotoxic effects of CDDP and GnRHa is a compound of high patient compliance, the value of GnRHa as a tumor sensitizer to CDDP should be further tested in clinical trials.
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PMID:In vitro effects of gonadotropin-releasing hormone (GnRH) analogue on cancer cell sensitivity to cis-platinum. 1038 Nov 37

Although gonadotropin-releasing hormone agonists (GnRHa) have been used in the therapy of the endocrine-dependent cancers, their biological mechanism remained obscure. We have studied the roles of mitogen-activated protein kinase family in the antiproliferative effect of GnRHa on the Caov-3 human ovarian cancer cell line. Reverse transcription-PCR assays confirmed mRNA for GnRH receptor in Caov-3 cells. In the presence of 1 microM GnRHa, the proliferation of cells was significantly reduced to 76% of controls after 24 h, and the effect was sustained up to 4 days. Although GnRHa had no effect on the activation of the Jun N-terminal kinase (JNK), treatment of Caov-3 cells with GnRHa activated extracellular signal-regulated protein kinase (ERK), and its effect was more than that induced by GnRH. Activation of ERK by GnRHa occurred within 5 min, with the maximum occurring at 3 h and sustained until 24 h. GnRHa also activated ERK kinase (mitogen-activated protein/ERK kinase) and resulted in an increase in phosphorylation of son of sevenless (Sos), and Shc. Furthermore, we examined the mechanism by which GnRHa induced ERK activation. Both pertussis toxin (10 ng/ml), which inactivates Gi/Go proteins, and expression of a peptide derived from the carboxyl terminus of the beta-adrenergic receptor kinase I, which specifically blocks signaling mediated by the betagamma subunits of G proteins, blocked the GnRHa-induced ERK activation. Phorbol 12-myristate 13-acetate (PMA) also induced the ERK activity, but pretreatment of the cultured cells with PMA to down-regulate protein kinase C did not abolish the activation of ERK by GnRHa. Elimination of extracellular Ca2+ by EGTA also did not abolish the activation of ERK by GnRHa. To examine the role of ERK cascade in the antiproliferative effect of GnRHa, PD98059, an inhibitor of mitogen-activated protein/ERK kinase, was used. This inhibitor canceled the antiproliferative effect of GnRHa and apparently reversed the GnRH-induced dephosphorylation of the retinoblastoma protein, the hyperphosphorylation of which is a hallmark of G1-S transition in the cell cycle. These results provide evidence that GnRHa stimulation of ERK activity may be mediated by Gbetagamma protein, not by PMA-sensitive protein kinase C nor extracellular Ca2+ in the Caov-3 human ovarian cancer cell line, suggesting that this cascade may play an important role in the antiproliferative effect of GnRHa.
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PMID:Role of mitogen-activated protein kinase/extracellular signal-regulated kinase cascade in gonadotropin-releasing hormone-induced growth inhibition of a human ovarian cancer cell line. 1053 88

Lysophosphatidic acid (LPA) mediates pleomorphic effects on multiple cell lineages, including an increased proliferative response of ovarian cancer cells both in vitro and in vivo, at least in part through the novel expression of LPA receptors. Thus, LPA hydrolysis is necessary to limit the duration of LPA's action on multiple cell types, including ovarian cancer cells. We determined the principal mechanism of LPA hydrolysis by ovarian cancer cells and its regulation by GnRH, which is known to have antiproliferative actions on ovarian carcinomas. LPA-hydrolyzing activity in cell membranes of ovarian cancer specimens was assessed by measuring the conversion of exogenous [3H-oleoyl]LPA to [3H]oleic acid or mono[3H-oleoyl]glycerol. Approximately 98% of LPA hydrolysis could be accounted for by the dephosphorylation of LPA to yield monoglyceride, with the deacylation reaction accounting for less than 1% of LPA hydrolysis. The phosphatase activity in the plasma membrane ovarian cancer cells was approximately 2.5- and 8-fold higher than those in microsome and homogenate fractions, respectively. The membrane phosphatase was Mg2+ independent and insensitive to inhibition by N-ethylmaleimide, characteristics suggestive of phosphatidic acid phosphatase activity. Incubation of membranes from GnRH receptor-positive ovarian cancer specimens with the GnRH agonist, buserelin, induced a dose-dependent increase in LPA phosphatase activity, with a half-maximal effect occurring with 30 nmol/L buserelin. The stimulatory action of buserelin could be neutralized by displacement of GnRH from its receptor by the GnRH antagonist, antide. The plasma membranes from GnRH receptor-negative ovarian cancer specimens did not respond to GnRH stimulation. LPA phosphatase activity was also increased when the ovarian cancer cell line Caov-3 was exposed to GnRH agonist in intact cells before assay of cell membranes. These data demonstrate that LPA is hydrolyzed in the plasma membrane of ovarian cancer cells by the action of LPA phosphatase and provide initial evidence for functional coupling of LPA phosphatase to GnRH receptor occupancy.
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PMID:A gonadotropin-releasing hormone-responsive phosphatase hydrolyses lysophosphatidic acid within the plasma membrane of ovarian cancer cells. 1099 36

In the present study, we investigated the expression of estrogen receptors (ERalpha and ERbeta) in human ovarian surface epithelial (hOSE) cells and the ovarian cancer cell line, OVCAR-3, and provided novel evidence that estrogen may have a growth regulatory effect in these cells. Expression levels of ERalpha messenger RNA (mRNA) were 1.5-fold higher in OVCAR-3 cells than in hOSE cells, as revealed by semiquantitative RT-PCR and Southern blot analysis. A significant increase (3.3-fold) in ERss mRNA levels was observed in OVCAR-3 cells compared with hOSE cells. In parallel with mRNA levels, expression levels of ERalpha and ERbeta proteins were also higher in OVCAR-3 cells compared with hOSE cells. We recently proposed that GnRH and its receptor may have an autocrine role in hOSE and ovarian cancer cells. To determine whether estrogen regulates GnRH and GnRH receptor (GnRHR), hOSE and OVCAR-3 cells were treated with various concentrations of 17beta-estradiol for 24 h. Expression levels of GnRH and GnRHR mRNA were examined using quantitative and competitive RT-PCR, respectively. Treatment with 17beta-estradiol induced a significant down-regulation of GnRH mRNA in OVCAR-3 cells, but not in hOSE cells and of GnRHR mRNA in both hOSE and OVCAR-3 cells. Tamoxifen, an estrogen antagonist, prevented the effects of 17ssestradiol, suggesting that estradiol action is mediated via the ER. Finally, the effect of estrogen on the growth of hOSE and OVCAR-3 cells was investigated. The cells were treated with various concentrations of 17ss-estradiol, and the proliferative index of cells was measured using [(3)H]thymidine incorporation and DNA fluorometric assays. 17beta-Estradiol stimulated the growth of OVCAR-3 cells in a dose- and time-dependent manner. In contrast, 17beta-estradiol failed to stimulate the growth of hOSE cells. As estrogen down-regulated GnRH and GnRHR mRNA, we investigated whether estrogen treatment blocks the growth inhibitory effect of a GnRH agonist in OVCAR-3 and hOSE cells. Cells were treated with 17beta-estradiol (10(-7) M) together with (D-Ala(6))-GnRH (10(-7) M), and the proliferative index of cells was measured. Pre- or cotreatment of cells with 17beta-estradiol significantly attenuated the growth inhibitory effect of the GnRH agonist in OVCAR-3 cells, whereas no effect of 17ss-estradiol treatment was observed in hOSE cells. To our knowledge, these results provide the first demonstration of a potential interaction between the estradiol/ER and GnRH/GnRHR systems, which may be important in the growth regulation of normal and neoplastic hOSE cells.
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PMID:Estradiol regulates gonadotropin-releasing hormone (GnRH) and its receptor gene expression and antagonizes the growth inhibitory effects of GnRH in human ovarian surface epithelial and ovarian cancer cells. 1115 28

Considering that the action of gonadotropin-releasing hormone (GnRH) may be mediated via different signaling pathways in extrapituitary tissues, in the present study we investigated the role of the human GnRH receptor (GnRHR) in activating mitogen-activated protein kinases (MAPKs), which regulate cell growth, division, and differentiation. The phosphorylation state of p44 and p42 MAPKs was examined using antibodies that distinguish phospho-p44/42 MAPK (P-MAPK, Thr(202)/Tyr(204)) from total p44/42 MAPK (T-MAPK, activated plus inactivated) in human ovarian and placental cells. Cell cultures were treated with various concentrations of a GnRH agonist, (D-Ala(6))-GnRH, for 5 min. (D-Ala(6))-GnRH stimulated a rapid activation of P-MAPK in human granulosa-luteal cells (hGLCs) and immortalized extravillous trophoblast (IEVT) cells. Interestingly, (D-Ala(6))-GnRH treatment of ovarian cancer (OVCAR-3) and placental carcinoma (JEG-3) cells induced a biphasic regulatory pattern in P-MAPK activity. In contrast, no change of T-MAPK levels was observed following addition of the GnRH agonist in the ovarian and placental cells examined. The physiological implication of MAPK activation by GnRH in the ovarian and placental cells was also investigated. Human GLCs were treated with (D-Ala(6))-GnRH for 24 h, and progesterone secretion was measured by an established RIA. (D-Ala(6))-GnRH induced a significant decrease in progesterone secretion with maximum inhibition (a 45% decrease over basal level) at 10(-7) M. This inhibitory effect was completely reversed by pretreatment with MAPK/ERK kinase 1 (MEK1) inhibitor (PD98059), suggesting the involvement of the MAPK pathway in hGLCs. Placental JEG-3 cells were treated with (D-Ala(6))-GnRH for 24 h, and betahCG mRNA level was measured using Northern blot analysis. (D-Ala(6))-GnRH stimulated the expression of betahCG mRNA to 160% of control value in JEG-3 cells. In contrast to the ovarian cells, pretreatment of JEG-3 cells with PD98059 failed to block the stimulatory effect of GnRH on betahCG mRNA level, suggesting that other signaling pathway(s) may play a more dominant role in GnRH-induced betahCG mRNA expression. To our knowledge, this is the first demonstration that (1) GnRH induces activation of the MAPK signaling pathway in normal and carcinoma cells of the human ovary and placenta, and (2) MAPK mediates the direct action of GnRH on progesterone production in hGLCs.
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PMID:Gonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cells. 1116 98

We have recently proposed an autocrine role of gonadotropin-releasing hormone (GnRH) and its receptor (GnRH-R) in human ovarian surface epithelium. In the present study, we examine the presence and role of a GnRH/GnRH-R loop in epithelial ovarian cancer cells, OVCAR-3. A dose-dependent biphasic response in GnRH and GnRH-R mRNA levels were observed after treating with GnRH agonist [GnRHa, (D-Ala6)-GnRH], for 24 h. High concentrations of GnRHa (10(-9) M and 10(-7)) decreased the GnRH and GnRH-R mRNA levels, whereas a low concentration (10(-11) M) resulted in an upregulation of GnRH and GnRH-R genes expression. Cotretment with the competitive antagonist, antide, prevented the biphasic effect induced by GnRHa, confirming the specificity of the response. In addition, GnRHa treatment resulted in a time- and dose-dependent inhibition on OVCAR-3 cells growth. A significant inhibition of proliferation was detected as early as the d 2 of treatment. Treatment with 10(-7) M GnRHa induced DNA fragmentation in OVCAR-3 cells, suggesting that the GnRHa-induced antiproliferation in OVCAR-3 cells was mediated by apoptosis. Again, this effect was prevented by cotreatment of antide. Taken together, our findings strongly support the notion that GnRH acts as an autocrine/paracrine regulator of ovarian cancer cell proliferation.
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PMID:Autocrine role of gonadotropin-releasing hormone and its receptor in ovarian cancer cell growth. 1121 41

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


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