High affinity binding and direct antiproliferative effects of luteinizing hormone-releasing hormone analogs in human endometrial cancer cell lines

Emons, Günter

doi:10.1210/jc.77.6.1458

Cited by 105 publications

(93 citation statements)

References 7 publications

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“…The human endometrial cancer cell lines Ishikawa, HEC-1A and Hec-1B and the ovarian cancer cell lines EFO-21, EFO-27, OVCAR-3, SK-OV-3 and BG-1 were obtained from American Type Culture Collection (ATCC, Manassas, Virginia, USA) or the sources detailed previously (2,3). The cells were cultured at 37 8C in a humidified atmosphere of 5% CO 2 in air as described previously (2 -4).…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

“…The GnRH-I antagonist cetrorelix (SB-75; [Ac-DNal (2) 1 , D-Phe(4Cl) 2 , D-Pal(3) 3 , D-Cit 6 , D-Ala 10 ]GnRH-I) was kindly provided by Zentaris (Frankfurt, Germany) and the GnRH-I agonist [D-Trp 6 ]GnRH (triptorelin; pGlu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH 2 ) was kindly provided by Ferring Pharmaceuticals (Copenhagen, Denmark). Human GnRH-II ( pGlu-HisTrp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH 2 ) was purchased from Bachem (Heidelberg, Germany).…”

Section: Gnrh Analoguesmentioning

confidence: 99%

“…The time-course and dose -response proliferation experiments were performed as described in detail previously (2,3). Briefly, 20 000 cells of each cell line were plated in four-well cluster dishes (Nunc, Roskilde, Denmark) and allowed to attach to the wells.…”

Section: Proliferation Assaysmentioning

confidence: 99%

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Antiproliferative effects of the GnRH antagonist cetrorelix and of GnRH-II on human endometrial and ovarian cancer cells are not mediated through the GnRH type I receptor

Gründker

Schlotawa

Viereck

et al. 2004

European Journal of Endocrinology

101

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Background: The majority of human endometrial and ovarian cancer cell lines express receptors for GnRH. Their proliferation is time-and dose-dependently reduced by GnRH-I and its superagonistic analogues. Recently, we have demonstrated that, in human endometrial and ovarian cancer cell lines except for the ovarian cancer cell line EFO-27, the GnRH-I antagonist cetrorelix has antiproliferative effects comparable to those of GnRH-I agonists, indicating that the dichotomy between GnRH-I agonists and antagonists might not apply to the GnRH system in cancer cells. We were also able to show that the proliferation of human endometrial and ovarian cancer cells was doseand time-dependently reduced by GnRH-II to a greater extent than by GnRH-I agonists. Objective: In this study we have assessed whether or not the antiproliferative effects of the GnRH-I antagonist cetrorelix in endometrial and ovarian cancer cells are mediated through the GnRH-I receptor. Methods: We analysed the antiproliferative effects of the GnRH-I agonist triptorelin, the GnRH-I antagonist cetrorelix and GnRH-II in a panel of endometrial and ovarian cancer cell lines expressing GnRH-I receptors, in the SK-OV-3 ovarian cancer cell line that does not express GnRH-I receptors, and in four GnRH-I receptor positive GnRH-I receptor knockout cell lines. Results: We found that, after knockout of the GnRH-I receptor, the antiproliferative effects of the GnRH-I agonist triptorelin were abrogated, whereas those of the GnRH-I antagonist cetrorelix and of GnRH-II persisted. Conclusions: These data suggest that, in endometrial and ovarian cancer cells, the antiproliferative effects of cetrorelix and of GnRH-II are not mediated through the GnRH-I receptor.

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Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

Section: Gnrh Analoguesmentioning

confidence: 99%

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Antiproliferative effects of the GnRH antagonist cetrorelix and of GnRH-II on human endometrial and ovarian cancer cells are not mediated through the GnRH type I receptor

Gründker

Schlotawa

Viereck

et al. 2004

European Journal of Endocrinology

101

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“…The in vivo physiological response to GnRH administration is an initial rise followed by suppression of LH and FSH secretion (Dowsett et al, 1988). Emons et al (1993) found two types of GnRH binding sites in the HEC-1A and Ishikawa endometrial cancer cell lines; specific high affinity GnRH receptors were also found in the DU-145 prostate tumours (Lamharzi et al, 1998). However, we found no functional GnRH receptor in normal or malignant endometrium and no direct growth modulating effect in vitro on endometrial cancer cells (Chatzaki et al, 1996).…”

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confidence: 99%

Regulation of endometrial cancer cell growth by luteinizing hormone (LH) and follicle stimulating hormone (FSH)

et al. 2000

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Endometrial cancer occurs most commonly in postmenopausal women and is therefore coincidentally associated with elevated plasma LH and FSH levels (Nagamani et al, 1993). LH and FSH secretion is partly controlled by hypothalamic gonadotrophin releasing hormone (GnRH) and it is notable that recurrent endometrial cancer can be treated with GnRH analogues (Gallagher et al, 1991). However, the exact mechanism by which these analogues exert their clinical effect on endometrial cancer cell growth is not fully understood. The in vivo physiological response to GnRH administration is an initial rise followed by suppression of LH and FSH secretion (Dowsett et al, 1988). Emons et al (1993) found two types of GnRH binding sites in the HEC-1A and Ishikawa endometrial cancer cell lines; specific high affinity GnRH receptors were also found in the DU-145 prostate tumours (Lamharzi et al, 1998). However, we found no functional GnRH receptor in normal or malignant endometrium and no direct growth modulating effect in vitro on endometrial cancer cells (Chatzaki et al, 1996).In this study we explore the hypothesis that the antitumour activity of GnRH is an indirect consequence of reducing circulating LH and FSH levels. We describe the growth response of endometrial cancer cells to administration of LH and FSH; the second messenger response and the expression of LH and FSH receptors by these cells. MATERIALS AND METHODS Cell linesThe human endometrial adenocarcinoma cell line Ishikawa (Nishida et al, 1985) was a gift from Dr J White (Department of Reproductive Physiology, Hammersmith Hospital, London, UK) and the human endometrial papillary adenocarcinoma cell line HEC-1A was obtained from the American Type Culture Collection (Bethesda, MD). The human embryonic kidney cell lines 293L and 293F derived from 293 cells after stable transfection with LH and FSH receptor cDNA respectively were donated by Dr D Segaloff (University of Iowa College of Medicine, Iowa, USA). LH and FSHPituitary-derived LH and FSH were obtained from Sigma (Dorset, UK) and recombinant human LH and FSH were obtained from Dr M Page (Serono). Growth experiments293, 293L and 293F cells were grown in phenol-red free DMEM media (Sigma-Aldrich Company Ltd, Dorset, UK) supplemented with 5% heat-inactivated newborn calf serum (NCS), gentamycin, 10 mM HEPES, 2 mM glutamine plus antibiotic/antimycotic solution (Sigma, Dorset, UK). Ishikawa cells were grown in phenolred free DMEM nutrient mixture F-12 Ham media (Sigma, Dorset, Summary Gonadotrophin releasing hormone analogues (GnRHa) have been used to treat recurrent endometrial cancer. However, the mode of action is uncertain. Our previous studies showed no direct effect of GnRHa on endometrial cancer cell growth in vitro. We have now examined the effect of luteinizing hormone (LH) and follicle stimulating hormone (FSH) on endometrial cancer cell growth. The aim was to determine whether suppression of pituitary LH and FSH by GnRHa could explain the tumour regression seen in up to 44% of patients treated with this drug. We ...

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“…The presence of the LHRH receptor has prompted many researchers to investigate agonists and antagonists of LHRH-R and study the responses in multiple tumors. In a majority of cases, receptor suppression caused inhibition of cellular proliferation [31,32]. LHRH agonists have been used clinically in the treatment of prostate, breast and gynecological cancers and have produced excellent clinical results [33][34][35].…”

Section: Discussionmentioning

confidence: 99%

LHRH receptor expression in sarcomas of bone and soft tissue

Deivaraju¹,

Temple²,

Block³

et al. 2016

Hormone Molecular Biology and Clinical Investigation

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Aim: Luteinizing hormone releasing hormone (LHRH) is a neurohormone, secreted by the hypothalamus, which regulates the secretion of gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary. LHRH acts by binding to receptors located in the pituitary gland. These receptors (LHRH receptors) have also been found in the cytoplasm of many tumor cells that involve both the reproductive and non-reproductive organs. These receptors have been demonstrated in prostate and breast cancers, endometrial carcinomas, renal cell carcinoma, lymphoma, carcinoma of liver, pancreas and skin. So far, the expression of LHRH receptors on sarcomas (i.e. malignant tumors of mesenchymal origin) has not been studied, except for endometrial sarcomas. It has also been demonstrated that both LHRH agonists and antagonists can down-regulate these receptors and thus inhibit these tumor cells. Another major therapeutic implication is that these receptors can be targeted specifically by peptides conjugated to anti-cancer drugs. The purpose of this study was to determine if LHRH receptors are expressed in primary and/or metastatic sarcomas of human origin. Methods: We looked at LHRH receptor expression in 38 consecutive sarcoma specimens, using immunohistochemistry. The specimens were either from office biopsy or from resected tumor; these were confirmed as sarcomas by histopathological examination. The receptor staining characteristics and the staining intensity were also documented. The pattern of staining was classified either as "focal or diffuse staining of the cytoplasm" and the intensity of staining was graded on a scale from 1+ to 4+. Results: Positive receptor staining was seen in 25 of the 38 (66%) specimens. Twelve of the specimens stained diffusely and 13 had focally positive staining. Three tumors had 1+ staining, 10 had 2+ staining, six had 3+ staining, and six tumors had 4+ staining. The tumors included undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, myofibroblastic sarcoma, myxofibrosarcoma, liposarcoma, dermatofibrosarcoma protuberans, metastatic chondrosarcoma and chordoma. Conclusion: Sarcomas express LHRH receptors with a varying incidence and degree. Our study suggests that those sarcomas that are LHRH receptor positive could potentially be treated with targeted chemotherapy.

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High affinity binding and direct antiproliferative effects of luteinizing hormone-releasing hormone analogs in human endometrial cancer cell lines

Cited by 105 publications

References 7 publications

Antiproliferative effects of the GnRH antagonist cetrorelix and of GnRH-II on human endometrial and ovarian cancer cells are not mediated through the GnRH type I receptor

Antiproliferative effects of the GnRH antagonist cetrorelix and of GnRH-II on human endometrial and ovarian cancer cells are not mediated through the GnRH type I receptor

Regulation of endometrial cancer cell growth by luteinizing hormone (LH) and follicle stimulating hormone (FSH)

LHRH receptor expression in sarcomas of bone and soft tissue

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