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Open Access 01-12-2003 | Review

Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer

Authors: Carsten Gründker, Günter Emons

Published in: Reproductive Biology and Endocrinology | Issue 1/2003

Abstract

The expression of GnRH (GnRH-I, LHRH) and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the ovary. The proliferation of human ovarian cancer cell lines is time- and dose-dependently reduced by GnRH and its superagonistic analogs. The classical GnRH receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH analogs in these cancer cells. The GnRH receptor rather interacts with the mitogenic signal transduction of growth-factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in downregulation of cancer cell proliferation. In addition GnRH activates nucleus factor κB (NFκB) and protects the cancer cells from apoptosis. Furthermore GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (JNK/AP-1) pathway independent of the known AP-1 activators, protein kinase (PKC) or mitogen activated protein kinase (MAPK/ERK).

Recently it was shown that human ovarian cancer cells express a putative second GnRH receptor specific for GnRH type II (GnRH-II). The proliferation of these cells is dose- and time-dependently reduced by GnRH-II in a greater extent than by GnRH-I (GnRH, LHRH) superagonists. In previous studies we have demonstrated that in ovarian cancer cell lines except for the EFO-27 cell line GnRH-I antagonist Cetrorelix has comparable antiproliferative effects as GnRH-I agonists indicating that the dichotomy of GnRH-I agonists and antagonists might not apply to the GnRH-I system in cancer cells. After GnRH-I receptor knock down the antiproliferative effects of GnRH-I agonist Triptorelin were abrogated while the effects of GnRH-I antagonist Cetrorelix and GnRH-II were still existing. In addition, in the ovarian cancer cell line EFO-27 GnRH-I receptor but not putative GnRH-II receptor expression was found. These data suggest that in ovarian cancer cells the antiproliferative effects of GnRH-I antagonist Cetrorelix and GnRH-II are not mediated through the GnRH-I receptor.

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Schally AV: Hypothalamic hormones from neuroendocrinology to cancer therapy. Anticancer Drugs. 1994, 5: 115-130.CrossRefPubMed

Stojilkovic SS, Catt KJ: Expression and signal transduction pathways of gonadotropin-releasing hormone receptors. Recent Prog Horm Res. 1995, 30: 161-205.

Stanislaus D, Pinter JH, Janovick JA, Conn PM: Mechanisms mediating multiple physiological responses to gonadotropin-releasing hormone. Mol Cell Endocrinol. 1998, 144: 1-10. 10.1016/S0303-7207(98)00126-9.CrossRefPubMed

Gründker C, Günthert AR, Westphalen S, Emons G: Biology of the GnRH system in human gynecological cancers. Eur J Endocrinol. 2002, 146: 1-14.CrossRefPubMed

Emons G, Ortmann O, Schulz KD, Schally AV: Growth-inhibitory actions of analogues of luteinizing hormone releasing hormone on tumor cells. Trends Endocrinol Metab. 1997, 8: 155-362.CrossRef

Emons G, Pahwa GS, Brack C, Sturm R, Oberheuser F, Knuppen R: Gonadotropin releasing hormone binding sites in human epithelial ovarian carcinomata. Eur J Cancer Clin Oncol. 1989, 25: 215-221.CrossRefPubMed

Pahwa GS, Vollmer G, Knuppen R, Emons G: Photoaffinity labelling of gonadotropin releasing hormone binding sites in human epithelial ovarian carcinomata. Biochem Biophys Res Commun. 1989, 161: 1086-1092.CrossRefPubMed

Thompson MA, Adelson MD, Kaufman LM: Lupron retards proliferation of ovarian tumor cells cultured in serum-free medium. J Clin Endocrinol Metab. 1991, 72: 1036-1041.CrossRefPubMed

Emons G, Ortmann O, Becker M, Irmer G, Springer B, Laun R, Hölzel F, Schulz KD, Schally AV: High affinity binding and direct antiproliferative effects of LHRH analogues in human ovarian cancer cell lines. Cancer Res. 1993, 54: 5439-5446.

10.

Ohno T, Imai A, Furui T, Takahashi K, Tamaya T: Presence of gonadotropin-releasing hormone and his messenger ribunucleic acid in human ovarian epithelial carcinoma. Am J Obstet Gynecol. 1993, 169: 605-610.CrossRefPubMed

11.

Yano T, Pinski J, Radulovic S, Schally AV: Inhibition of human epithelial ovarian cancer cell growth in vitro by agonistic and antagonistic analogues of luteinizing hormone-releasing hormone. Proc Natl Acad Sci USA. 1994, 91: 1701-1704.PubMedCentralCrossRefPubMed

12.

Yano T, Pinski J, Halmos G, Szepeshazi K, Schally AV: Inhibition of growth of OV-1063 human epithelial ovarian cancer xenografts in nude mice by treatment with luteinizing hormone-releasing hormone antagonist SB-75. Proc Natl Acad Sci USA. 1994, 91: 7090-7094.PubMedCentralCrossRefPubMed

13.

Kakar SS, Grizzle WE, Neill JD: The nucleotide sequence of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary. Mol Cell Endocrinol. 1994, 106: 145-149. 10.1016/0303-7207(94)90196-1.CrossRefPubMed

14.

Irmer G, Bürger C, Müller R, Ortmann O, Peter U, Kakar S, Neill JD, Schulz KD, Emons G: Expression of the messenger RNAs for luteinizing hormone-releasing hormone (LHRH) and its receptor in human ovarian epithelial carcinoma. Cancer Res. 1995, 55: 817-822.PubMed

15.

Völker P, Gründker C, Schmidt O, Schulz KD, Emons G: Expression of receptors for luteinizing hormone-releasing hormone in human ovarian and endometrial cancers: frequency, autoregulation and correlation with direct antiproliferative activity of LHRH analogues. Am J Obstet Gynecol. 2002, 186: 171-179. 10.1067/mob.2002.119633.CrossRefPubMed

16.

Dondi D, Limonta P, Moretti RM, Marelli MM, Garattini E, Motta M: Antiproliferative effects of luteinizing hormone-releasing hormone (LHRH) agonists on human androgen-independent prostate cancer cell line DU 145: Evidence for an autocrine-inhibitory LHRH loop. Cancer Res. 1994, 54: 4091-4095.PubMed

17.

Emons G, Schally AV: The use of luteinizing hormone-releasing hormone agonists and antagonists in gynecological cancers. Hum Reprod. 1994, 9: 1364-1379.PubMed

18.

Emons G, Schröder B, Ortmann O, Westphalen S, Schulz KD, Schally AV: High affinity binding and direct antiproliferative effects of luteinizing hormone-releasing hormone analogs in human endometrial cancer cell lines. J Clin Endocrinol Metab. 1993, 77: 1458-1464. 10.1210/jc.77.6.1458.PubMed

19.

Miller WR, Scott WN, Morris R, Fraser HM, Sharpe RM: Growth of human breast cancer cells inhibited by luteinizing hormone-releasing hormone agonist. Nature. 1985, 313: 231-233.CrossRefPubMed

20.

Shibata S, Sato H, Ota H, Karube A, Takahashi O, Tanaka T: Involvement of annexin V in antiproliferative effects of gonadotropin-releasing hormone agonists on human endometrial cancer cell line. Gynecol Oncol. 1997, 66: 217-221. 10.1006/gyno.1997.4746.CrossRefPubMed

21.

Kleinman D, Douvdevani A, Schally AV, Levy J, Sharoni Y: Direct growth inhibition of human endometrial cancer cells by the gonadotropin-releasing hormone antagonist SB-75: role of apoptosis. Am J Obst Gynecol. 1994, 170: 96-102.CrossRef

22.

Pályi I, Vincze B, Kálnay A, Turi G, Mezo I, Teplan I, Seprodi J, Pato J, Mora M: Effect of gonadotropin releasing hormone analogs and their conjugates on gonadotropin-releasing hormone receptor-positive human cancer cell lines. Cancer Detect Prev. 1996, 20: 146-152.PubMed

23.

Connor JP, Buller RE, Conn PM: Effects of GnRH analogs on six ovarian cancer cell lines in culture. Gynecol Oncol. 1994, 54: 3215-3221.

24.

Manetta A, Gamboa-Vujicic L, Paredes P, Emma D, Liao S, Leong L, Asch B, Schally AV: Inhibition of growth of human ovarian cancer in nude mice by luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75). Fertil Steril. 1995, 63: 282-287.PubMed

25.

Chatzaki E, Bax CMR, Eidne KA, Anderson L, Grudzinskas JG, Gallagher CJ: The expression of gonadotropin-releasing hormone and its receptor in endometrial cancer and its relevance as an autocrine growth factor. Cancer Res. 1996, 56: 2055-2065.

26.

Emons G, Ortmann O, Irmer G, Müller V, Schulz KD, Schally AV: Treatment of ovarian cancer with LHRH antagonists. Treatment with GnRH Analogs: Controversies and Perspectives. Edited by: Filicori M, Flamigni C. 1996, Carnforth: Parthenon Publishing, 165-172.

27.

Loop SM, Gorder CA, Lewis SM, Saiers JH, Drivdahl RH, Ostenson RC: Growth inhibition of human prostatic cancer cells by an agonist of gonadotropin-releasing hormone. Prostate. 1995, 26: 179-188.CrossRefPubMed

28.

Motta M, Dondi D, Moretti M, Montagnani-Marelli M, Pimpinelli F, Maggi R, Limonta P: Role of growth factors, steroid and peptide hormones in the regulation of human prostatic tumor growth. J Steroid Biochem Mol Biol. 1996, 56: 107-111. 10.1016/0960-0760(95)00240-5.CrossRefPubMed

29.

Jungwirth A, Galvan G, Pinski J, Halmos G, Szepeshazi K, Cai RZ, Groot K, Schally AV: Luteinizing hormone releasing hormone antagonist Cetrorelix (SB-75) and bombesin antagonist RC-3940-II inhibit the growth of androgen-independent PC-3 prostate cancer in nude mice. Prostate. 1997, 32: 164-172. 10.1002/(SICI)1097-0045(19970801)32:3<164::AID-PROS2>3.3.CO;2-Z.CrossRefPubMed

30.

Jungwirth A, Pinski J, Galvan G, Halmos G, Szepeshazi K, Cai RZ, Groot K, Vadillo-Buenfil M, Schally AV: Inhibition of growth of androgen-independent DU-145 prostate cancer in vivo by luteinizing hormone-releasing hormone antagonist Cetrorelix and bombesin antagonists RC-3940-II and RC-3950-II. Eur J Cancer. 1997, 33: 1141-1148. 10.1016/S0959-8049(97)00072-5.CrossRefPubMed

31.

Montagnani-Marelli M, Moretti RM, Dondi D, Limonta P, Motta M: Effects of LHRH agonists on the growth of human prostatic tumor cells: "in vitro" and "in vivo" studies. Arch Ital Urol Androl. 1997, 69: 257-263.PubMed

32.

Qayum A, Gullick W, Clayton RC, Sikora K, Waxman J: The effects of gonadotropin-releasing hormone analogues in prostate cancer are mediated through specific tumor receptors. Br J Cancer. 1990, 62: 96-99.PubMedCentralCrossRefPubMed

33.

Emons G, Weiβ S, Ortmann O, Gründker C, Schulz KD: Luteinizing hormone-releasing hormone (LHRH) might act as a negative autocrine regulator of proliferation of human ovarian cancer. Eur J Endocrinol. 2000, 142: 665-670.CrossRefPubMed

34.

Arencibia JM, Schally AV: Luteinizing hormone-releasing hormone as an autocrine growth factor in ES-2 ovarian cancer cell line. Int J Oncol. 2000, 16: 1009-1013.PubMed

35.

Emons G, Müller V, Ortmann O, Grossmann G, Trautner U, von Stuckrad B, Schulz KD, Schally AV: Luteinizing hormone-releasing hormone agonist triptorelin antagonizes signal transduction and mitogenic activity of epidermal growth factor in human ovarian and endometrial cancer cell lines. Int J Oncol. 1996, 9: 1129-1137.PubMed

36.

Gründker C, Völker P, Günthert AR, Emons G: Antiproliferative signaling of LHRH in human endometrial and ovarian cancer cells through G-protein αi-mediated activation of phosphotyrosine phosphatase. Endocrinology. 2001, 142: 2369-2380. 10.1210/en.142.6.2369.PubMed

37.

Lee MT, Liebow C, Kramer AR, Schally AV: Effects of epidermal growth factor and analogues of luteinizing hormone-releasing hormone and somatostatin on phosphorylation of tyrosine residues of specific substrates in various tumors. Proc Natl Acad Sci USA. 1991, 88: 1656-1660.PubMedCentralCrossRefPubMed

38.

Furui T, Imai A, Takagi H, Horibe S, Fuseya T, Tamaya T: Phosphotyrosine phosphatase activity in membranes from endometrial carcinoma. Oncology Reports. 1995, 2: 1055-1057.PubMed

39.

Imai A, Takagi H, Furui T, Horibe S, Fuseya T, Tamaya T: Evidence for coupling of phosphotyrosine phosphatase to gonadotropin-releasing hormone receptor in ovarian carcinoma membrane. Cancer. 1996, 77: 132-137. 10.1002/(SICI)1097-0142(19960101)77:1<132::AID-CNCR22>3.0.CO;2-5.CrossRefPubMed

40.

Imai A, Takagi H, Horibe S, Fuseya T, Tamaya T: Coupling of gonadotropin releasing hormone receptor to Gi protein in human reproductive tract tumors. J Clin Endocrinol Metab. 1996, 81: 3249-3253. 10.1210/jc.81.9.3249.PubMed

41.

Gründker C, Völker P, Schulz KD, Emons G: Luteinizing Hormone-releasing Hormone (LHRH) Agonist Triptorelin and Antagonist Cetrorelix inhibit EGF-induced c-fos Expression in Human Gynecological Cancers. Gynecol Oncol. 2000, 78: 194-202. 10.1006/gyno.2000.5863.CrossRefPubMed

42.

Moretti RM, Montagnani-Marelli M, Dondi D, Poletti A, Martini L, Motta M, Limonta P: Luteinizing hormone-releasing hormone agonists interfere with the stimulatory actions of epidermal growth factor in human prostatic cancer cell lines, LNCaP and DU 145. J Clin Endocrinol Metab. 1996, 81: 3930-3937. 10.1210/jc.81.11.3930.PubMed

43.

Shirahige Y, Cook C, Pinski J, Halmos G, Nair R, Schally AV: Treatment with luteinizing hormone-releasing hormone antagonist SB-75 decreases levels of epidermal growth factor receptor and its mRNA in OV-1063 human epithelial ovarian cancer xenografts in nude mice. Int J Oncol. 1994, 5: 1031-1035.PubMed

44.

Kéri G, Balogh A, Szöke B, Téplan J, Csika O: Gonadotropin-releasing hormone analogues inhibit cell proliferation and activate signal transduction pathways in MDA-MB-231 human breast cancer cell lines. Tumour Biol. 1991, 12: 61-67.CrossRefPubMed

45.

Liebow C, Lee MT, Kramer AR, Schally AV: Regulation of luteinizing hormone-releasing hormone receptor binding by heterologous receptor-stimulated tyrosine phosphorylation. Proc Natl Acad Sci USA. 1991, 88: 2244-2248.PubMedCentralCrossRefPubMed

46.

Hershkovitz E, Marbach M, Bosin M, Levy J, Roberts C, Le Roith D, Schally AV, Sharoni Y: Luteinizing hormone-releasing hormone antagonists interfere with autocrine and paracrine growth stimulation of MCF-7 mammary cancer cells by insulin like growth factors. J Clin Endocrinol Metab. 1993, 77: 963-968. 10.1210/jc.77.4.963.PubMed

47.

Imai A, Horibe S, Takagi A, Ohno T, Tamaya T: Frequent expression of Fas in gonadotropin-releasing hormone receptor-bearing tumors. Eur J Obstet Gynecol Reprod Biol. 1997, 74: 73-78. 10.1016/S0301-2115(97)02750-4.CrossRefPubMed

48.

Imai A, Takagi A, Horibe S, Takagi H, Tamaya T: Evidence for tight coupling of gonadotropin-releasing hormone receptor to stimulate Fas ligand expression in reproductive tumors: possible mechanism for hormonal control of apoptotic cell death. J Clin Endocrinol Metab. 1998, 83: 127-431.

49.

Imai A, Takagi A, Horibe S, Takagi H, Tamaya T: Fas and Fas-ligand system may mediate antiproliferative activity of gonadotropin-releasing hormone receptor in endometrial cancer cells. Int J Oncol. 1998, 13: 97-100.PubMed

50.

Gründker C, Schulz K, Günthert AR, Emons G: Luteinizing hormone-releasing hormone induces nuclear factor kappaB-activation and inhibits apoptosis in ovarian cancer cells. J Clin Endocrinol Metab. 2000, 85: 3815-3820. 10.1210/jc.85.10.3815.PubMed

51.

Gründker C, Schlotawa L, Viereck V, Emons G: Protein kinase C (PKC)-independent stimulation of activator protein-1 (AP-1) and c-Jun N-terminal kinase (JNK) activity in human endometrial cancer cells by luteinizing hormone-releasing hormone (LHRH) agonist Triptorelin. Eur J Endocrinol. 2001, 145: 651-658.CrossRefPubMed

52.

Yamauchi J, Itoh H, Shinoura H, Miyamoto Y, Hirasawa A, Kaziro Y, Tsujimoto G: Involvement of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase in α1B-adrenergic receptor/Gαq-induced inhibition of cell proliferation. Biochem Biophys Res Commun. 2001, 281: 1019-1023. 10.1006/bbrc.2001.4472.CrossRefPubMed

53.

Bigsby RM, Li A: Differentially regulated immediate early genes in the rat uterus. Endocrinology. 1994, 134: 1820-1826. 10.1210/en.134.4.1820.PubMed

54.

Seppänen M, Lin L, Punnonen J, Grénman S, Punnonen R, Vihko K: Regulation of UT-OC-3 ovarian carcinoma cells by cytokines: inhibitory effects on cell proliferation and activation of transcription factors AP-1 and NF-kappaB. Eur J Endocrinol. 2000, 142: 393-401.CrossRefPubMed

55.

Günthert AR, Gründker C, Hollmann K, Emons G: Luteinizing hormone-releasing hormone induces JunD-DNA binding and extends cell cycle in human ovarian cancer cells. Biochem Biophys Res Commun. 2002, 294: 11-15. 10.1016/S0006-291X(02)00427-8.CrossRefPubMed

56.

Miyamoto K, Hasegawa Y, Nomura M, Igarashi M, Kangawa K, Matsuo H: Identification of the second gonadotropin-releasing hormone in chicken hypothalamus: evidence that gonadotropin secretion is probably controlled by two distinct gonadotropin-releasing hormones in avian species. Proc Natl Acad Sci USA. 1984, 81: 3874-3878.PubMedCentralCrossRefPubMed

57.

Sower SA, Chiang YC, Lovas S, Conlon JM: Primary structure and biological activity of a third gonadotropin-releasing hormone from lamprey brain. Endocrinology. 1993, 132: 1125-1131. 10.1210/en.132.3.1125.PubMed

58.

White RB, Eisen JA, Kasten TL, Fernald RD: Second gene for gonadotropin-releasing hormone in humans. Proc Natlional Acad Sci USA. 1998, 95: 305-309. 10.1073/pnas.95.1.305.CrossRef

59.

Urbanski HF, White RB, Fernald RD, Kahoma SG, Garyfallou VT, Densmore VS: Regional expression of mRNA encoding a second form of gonadotropin-releasing hormone in the macaque brain. Endocrinology. 1999, 140: 1945-1948. 10.1210/en.140.4.1945.CrossRefPubMed

60.

Kang SK, Tai CJ, Nathwani PS, Leung PC: Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid in human granulosa-luteal cells. Endocrinology. 2001, 142: 182-192. 10.1210/en.142.1.182.PubMed

61.

Millar RP, Lowe S, Conklin D, Pawson A, Maudsley S, Troskie B, Ott T, Millar M, Lincoln G, Sellar R, Faurholm B, Scobie G, Kuestner R, Terasawa E, Katz A: A novel mammalian receptor for the evolutionarily conserved type II GnRH. Proc Natl Acad Sci U S A. 2001, 98: 9636-9641. 10.1073/pnas.141048498.PubMedCentralCrossRefPubMed

62.

Neill JD, Duck LW, Sellers JC, Musgrove LC: A gonadotropin-releasing hormone (GnRH) receptor specific for GnRH II in primates. Biochem Biophys Res Commun. 2001, 282: 1012-1018. 10.1006/bbrc.2001.4678.CrossRefPubMed

63.

Gründker C, Günthert AR, Millar RP, Emons G: 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. J Clin Endocrinol Metab. 2002, 87: 1427-1430. 10.1210/jc.87.3.1427.CrossRefPubMed

64.

Morgan K, Conklin D, Pawson AJ, Sellar R, Ott TR, Millar RP: A transcriptionally active human type II gonadotropin-releasing hormone receptor gene homolog overlaps two genes in the antisense orientation on chromosome 1q.12. Endocrinology. 2003, 144: 423-436. 10.1210/en.2002-220622.CrossRefPubMed

Title: Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer
Authors: Carsten Gründker
Günter Emons
Publication date: 01-12-2003
Publisher: BioMed Central
Published in: Reproductive Biology and Endocrinology / Issue 1/2003
Electronic ISSN: 1477-7827
DOI: https://doi.org/10.1186/1477-7827-1-65

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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