Journal of Embryo Transfer (한국수정란이식학회지)

The Korean Society of Embryo Transfer (한국수정란이식학회)
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Gonadotropin-releasing Hormone and Its Receptor as a Therapeutic Concept in the Progression of Epithelial Ovarian Cancer

  • Kim, Ki-Yon (Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia) ;
  • Choi, Kyung-Chul (Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University)
  • Published : 2009.03.31
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Abstract

Ovarian cancer is a significant cause of cancer-related death in women, but the main biological causes remain open questions. Hormonal factors have been considered to be an important determinant causing ovarian cancer. Recent studies have shown that gonadotropin-releasing hormone (GnRH)-I and its analogs have clinically therapeutic value in the treatment of ovarian cancer. In addition, numerous studies have shown that the potential of GnRH-II in normal reproductive system or reproductive disorder. GnRH-I receptors have been detected in approximately 80% of ovarian cancer biopsy specimens as well as normal ovarian epithelial cells and immortalized ovarian surface epithelium cells. GnRH-II receptors have also been found to be more widely expressed than GnRH-I receptors in mammals, suggesting that GnRH receptors may have additional functions in reproductive system including ovarian cancer. The signal transduction pathway following the binding of GnRH to GnRH receptor has been extensively studied. The activation of protein kinase A/C (PKA/PKC) pathway is involved in the GnRH-I induced anti-proliferative effect in ovarian cancer cells. In addition, GnRH-I induced mitogen-activated protein kinase (MAPK) activation plays a role in anti-proliferative effect and apoptosis in ovarian cancer cells and the activation of transcriptional factors related to cellular responses. However, the role of GnRH-I and II receptors, there are discrepancies between previous reports. In this review, the role of GnRH in ovarian cancer and the mechanisms to induce anti-proliferation were evaluated.

Keywords

References

  1. Alblas J, Slager-Davidov R, Steenbergh P, Sussenbach J and van der Burg B. 1998. The role of MAP kinase in TPA-mediated cell cycle arrest of human breast cancer cells. Oncogene 16:131-139 https://doi.org/10.1038/sj.onc.1201485
  2. Anderson L, Milligan G and Eidne K.A. 1993. Characterization of the gonadotrophin-releasing hormone receptor in alpha T3-1 pituitary gonadotroph cells. J. Endocrinol. 136:51-58 https://doi.org/10.1677/joe.0.1360051
  3. Andrews WV and Conn PM. 1986. Gonadotropin-releasing hormone stimulates mass changes in phosphoinositides and diacylglycerol accumulation in purified gonadotrope cell cultures. Endocrinology 118:1148-1158 https://doi.org/10.1210/endo-118-3-1148
  4. Benard O, Naor Z and Seger R. 2001. Role of Dynamin, Src, and Ras in the protein kinase C-mediated activation of ERK by gonadotropin-releasing hormone. J. BioI. Chem. 276:4554-4563 https://doi.org/10.1074/jbc.M006995200
  5. Birnbaumer L. 1992. Receptor-to-effector signaling through G proteins: roles for beta gamma dimers as well as alpha subunits. Cell 71:1069-1072 https://doi.org/10.1016/S0092-8674(05)80056-X
  6. Bourne GA, Regiani S, Payne AH and Marshall JC. 1980. Testicular GnRH receptors--characterization and localization on interstitial tissue. J. Clin. Endocrinol. Metab. 51: 407-409 https://doi.org/10.1210/jcem-51-2-407
  7. Burgus R, Butcher M, Amoss M, Ling N, Monahan M, Rivier J, Fellows R, Blackwell R, Vale W and Guillemin R. 1972. Primary structure of the ovine hypothalamic luteinizing hormone-releasing factor (LRF) (LH-hypothalamus-LRF-gas chromatography-mass spectrometry-decapeptide-Edman degradation). Proc. Natl. Acad. Sci. USA 69:278-282 https://doi.org/10.1073/pnas.69.1.278
  8. Cavigelli M, Dolfi F, Claret FX and Karin M. 1995. Induction of c-fos expression through JNK-mediated TCF/Elk-l phosphorylation. EMBO 14:5957-5964
  9. Cesnjaj M, Catt KJ and Stojilkovic SS. 1995. Coordinate actions of calcium and protein kinase-C in the expression of primary response genes in pituitary gonadotrophs. Endocrinology 135:692-701 https://doi.org/10.1210/en.135.2.692
  10. Chamson-Reig A, Sorianello EM, Catalano PN, Fernandez MO, Pignataro OP, Libertun C and Lux-Lantos VA. 2003. Gonadotropin-releasing hormone signaling pathways in an experimental ovarian tumor. Endocrinology 144:2957-2966 https://doi.org/10.1210/en.2003-0011
  11. Chao DT and Korsmeyer SJ. 1998. BCL-2 family: regulators of cell death. Annu. Rev. Immunol. 16:395-419 https://doi.org/10.1146/annurev.immunol.16.1.395
  12. Choi KC, Auersperg N and Leung PC. 2001. Expression and antiproliferative effect of a second form of gonadotropin releasing hormone in normal and neoplastic ovarian surface epithelial cells. J. Clin. Endocrinol Metab. 86:5075-5078 https://doi.org/10.1210/jc.86.10.5075
  13. Choi KC, Kang SK, Tai CJ, Auersperg N and Leung PC. 2002. Follicle-stimulating hormone activates mitogen-activated protein kinase in preneoplastic and neoplastic ovarian surface epithelial cells. J. Clin. Endocrinol. Metab. 87:2245-2253 https://doi.org/10.1210/jc.87.5.2245
  14. Clayton RN and Catt KJ. 1980. Receptor-binding affinity of gonadotropin-releasing hormone analogs: Analysis by radioligand-receptor assay. Endocrinology 106:1154-1159 https://doi.org/10.1210/endo-106-4-1154
  15. Clayton RN, Harwood JP and Catt KJ. 1979. Gonadotropin-releasing hormone analogue binds to luteal cells and inhibits progesterone production. Nature 282:90-92 https://doi.org/10.1038/282090a0
  16. Clayton RN, Solano AR, Garcia-Vela A, Dufau ML and Catt KJ. 1980. Regulation of pituitary receptors for gonadotropin-releasing hormone during the rat estrous cycle. Endocrinology 107:699-706 https://doi.org/10.1210/endo-107-3-699
  17. Cobb MH and Goldsmith EJ. 1995. How MAP kinases are regulated. J. Biol, Chem. 270:14843-14846 https://doi.org/10.1074/jbc.270.25.14843
  18. Currie AJ, Fraser HM and Sharpe RM. 1981. Human placental receptors for luteinizing hormone releasing hormone. Biochem. Biophys. Res. Commun. 99:332-338 https://doi.org/10.1016/0006-291X(81)91749-6
  19. Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M and Davis RJ. 1994. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76:1025-1037 https://doi.org/10.1016/0092-8674(94)90380-8
  20. Dikic I and Blaukat A. 1999. Protein tyrosine kinase-mediated pathways in G protein-coupled receptor signaling. Cell Biochem. Biophys. 30:369-387 https://doi.org/10.1007/BF02738120
  21. Dondi D, Moretti RM, Marelli MM, Motta M and Limonta P. 1996. Growth factors in steroid-responsive prostatic tumor cells. Steroids 61:222-225 https://doi.org/10.1016/0039-128X(96)00018-9
  22. Downes GB and Gautam N. 1999. The G protein subunit gene families. Genomics 62:544-552 https://doi.org/10.1006/geno.1999.5992
  23. Drissi H, Lasmoles F, Le Mellay V, Marie PJ and Lieberherr M. 1998. Activation of phospholipase C-beta 1 via Galpha q/11 during calcium mobilization by calcitonin gene-related peptide10.1074/jbc.273.32.20168. J. Biol. Chem. 273: 20168-20174
  24. Emons G, Muller V, Ortmann O and Schulz KD. 1998. Effects of LHRH-analogues on mitogenic signal transduction in cancer cells. J. Steroid. Biochem. Mol. BioI. 65:199-206 https://doi.org/10.1016/S0960-0760(97)00189-1
  25. Emons G, Ortmann O, Pahwa GS, Hackenberg R, Oberheuser F and Schulz KD. 1992. Intracellular actions of gonadotropic and peptide hormones and the therapeutic value of GnRH-agonists in ovarian cancer. Acta. Obstet. Gynecol. Scand. Suppl. 155:31-38
  26. Enomoto M, Endo D, Kawashima S and Park MK. 2004. Human type II GnRH receptor mediates effects of GnRH on cell proliferation. Zoolog. Sci. 21:763-770 https://doi.org/10.2108/zsj.21.763
  27. Fang X, Schummer M, Mao M, Yu S, Tabassam FH, Swaby R, Hasegawa Y, Tanyi JL, LaPushin R and Eder A. 2002. Lysophosphatidic acid is a bioactive mediator in ovarian-cancer. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1582:257-264 https://doi.org/10.1016/S1388-1981(02)00179-8
  28. Fekete M, Wittliff JL and Schally AV. 1989. Characteristics and distribution of receptors for [D-TRP6]-luteinizing hormone-releasing hormone, somatostatin, epidermal growth factor, and sex steroids in 500 biopsy samples of human breast cancer. J. Clin. Lab. Anal. 3:137-147 https://doi.org/10.1002/jcla.1860030302
  29. Florio S, Pagnini U, Crispino A, Pacilio C, Crispino L and Giordano A. 2002. GnRH and steroids in cancer. Front. Biosci. 7:d1590-1608 https://doi.org/10.2741/florio
  30. Furui T, Imai A and Tamaya T. 2002. Intratumoral level of gonadotropin-releasing hormone in ovarian and endometrial cancers. Oncol. Rep. 9:349-352
  31. Garrington TP and Johnson GL. 1999. Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr. Opin. Cell. BioI. 11:211-218 https://doi.org/10.1016/S0955-0674(99)80028-3
  32. Gille H, Kortenjann M, Thomae 0, Moomaw C, Slaughter C, Cobb MH and Shaw PE. 1995a. ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBO 14:951-962
  33. Gille H, Strahl T and Shaw PE. 1995b. Activation of ternary complex factor Elk-l by stress-activated protein kinases. Curr. Biol. 5:1191-1200 https://doi.org/10.1016/S0960-9822(95)00235-1
  34. Godwin AK, Testa JR, Handel LM, Liu Z, Vanderveer LA, Tracey PA and Hamilton TC. 1992. Spontaneous transformation of rat ovarian surface epithelial cells: association with cytogenetic changes and implications of repeated ovulation in the etiology of ovarian cancer. J. Natl. Cancer. Inst. 84:592-601 https://doi.org/10.1093/jnci/84.8.592
  35. Gohla A, Offermanns S, Wilkie TM and Schultz G. 1999. Differential involvement of Galphal2 and Galphal3 in receptor-mediated stress fiber formation. J. Biol. Chem. 274: 17901-17907 https://doi.org/10.1074/jbc.274.25.17901
  36. Grundker C, Gunthert AR, Millar RP and Emons G. 2002. 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. 87:1427-1430 https://doi.org/10.1210/jc.87.3.1427
  37. Grundker C, Schlotawa L, Viereck V and Emons G. 2001a. Protein kinase C-independent stimulation of activator protein-1 and c-Jun N-terminal kinase activity in human endometrial cancer cells by the LHRH agonist triptorelin. Eur. J. Endocrinol. 145(5):651-8:651-658 https://doi.org/10.1530/eje.0.1450651
  38. Grundker C, Schlotawa L, Viereck V, Eicke N, Horst A, Kairies B and Emons G. 2004. 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. Eur. J. Endocrinol. 151: 141-149 https://doi.org/10.1530/eje.0.1510141
  39. Grundker C, Schulz K, Gunthert AR and Emons G. 2000. Luteinizing hormone-releasing hormone induces nuclear factor {kappa}B-activation and inhibits apoptosis in ovarian cancer cells. J. Clin. Endocrinol. Metab. 85:3815- 3820 https://doi.org/10.1210/jc.85.10.3815
  40. Grundker C, Volker P and Emons G. 2001b. Antiproliferative signaling of luteinizing hormone-releasing hormone in human endometrial and ovarian cancer cells through G protein α i-mediated activation of phosphotyrosine phosphatase. Endocrinology 142:2369-2380 https://doi.org/10.1210/en.142.6.2369
  41. Gupta S, Campbell D, Derijard B and Davis RJ. 1995. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 267:389-393 https://doi.org/10.1126/science.7824938
  42. Harris D, Reiss Nand Naor Z. 1997. Differential activation of protein kinase C delta and epsilon gene expression by gonadotropin-releasing hormone in alphaT3-1 cells. Autoregulation by protein kinase C. J. Biol. Chem. 272:13534-13540 https://doi.org/10.1074/jbc.272.21.13534
  43. Harrison GS, Wierman ME, Nett TM and Glode LM. 2004. Gonadotropin-releasing hormone and its receptor in normal and malignant cells. Endocr. Relat. Cancer 11:725-748 https://doi.org/10.1677/erc.1.00777
  44. Hazum E and Conn PM. 1988. Molecular mechanism of gonadotropin releasing hormone (GnRH) action. I. The GnRH receptor. Endocr. Rev. 9:379-386 https://doi.org/10.1210/edrv-9-4-379
  45. Heger S, Muller M, Ranke M, Schwarz HP, Waldhauser F, Partsch CJ and Sippell WG. 2006. Long-term GnRH agonist treatment for female central precocious puberty does not impair reproductive function. Mol. Cell. Endocrinol. 25:217-220 https://doi.org/10.1016/j.mce.2006.04.012
  46. Herbst AL. 1994. The epidemiology of ovarian carcinoma and the current status of tumor markers to detect disease. Am. J. Obstet. Gynecol. 170:1099-1105 https://doi.org/10.1016/S0002-9378(94)70104-0
  47. Herskowitz I. 1995. MAP kinase pathways in yeast: for mating and more. Cell 80:187-197 https://doi.org/10.1016/0092-8674(95)90402-6
  48. Higashijima T, Burnier J and Ross EM. 1990. Regulation of Gi and Go by mastoparan, related amphiphilic peptides, and hydrophobic amines. Mechanism and structural determinants of activity. J. BioI. Chem. 265:14176-14186
  49. Hirai Y, Yasuhara T, Yoshida H, Nakajima T, Fujino M and Kitada C. 1979. A new mast cell degranulating peptide "mastoparan" in the venom of Vespula lewisii. Chem. Pharm. Bull. (Tokyo) 27:1942-1944 https://doi.org/10.1248/cpb.27.1942
  50. Homburg R. 2003. The management of infertility associated with polycystic ovary syndrome. Reprod. Biol. Endocrinol. 1:109 https://doi.org/10.1186/1477-7827-1-109
  51. Hong Y, Kwai WC, Hwa H-L, Chun P, Auersperg N and Leung PCK. 1998. Expression of the messenger RNA for gonadotropin-releasing hormone and its receptor in human cancer cell lines. Life Sci. 62:2015-2023 https://doi.org/10.1016/S0024-3205(98)00173-8
  52. Hsieh KP and Martin TF. 1992. Thyrotropin-releasing hormone and gonadotropin-releasing hormone receptors activate phospholipase C by coupling to the guanosine triphosphate-binding proteins Gq and G11. Molecular Endocrinology (Baltimore, Md.) 6:1673-1681 https://doi.org/10.1210/me.6.10.1673
  53. Huang SC, Tang MJ, Hsu KF, Cheng YM and Chou CY. 2002a. Fas and its ligand, caspases, and bcl-2 expression in gonadotropin-releasing hormone agonist-treated uterine leiomyoma. J. Clin. Endocrinol. Metab. 87:4580-4586 https://doi.org/10.1210/jc.2001-011968
  54. Huang YT, Hwang JJ, Lee LT, Liebow C, Lee PP, Ke FC, Lo TB, Schally AV and Lee MT. 2002b. Inhibitory effects of a luteinizing hormone-releasing hormone agonist on basal and epidermal growth factor-induced cell proliferation and metastasis-associated properties in human epidermoid carcinoma A431 cells. Int. J. Cancer 99:505-513 https://doi.org/10.1002/ijc.10373
  55. Hubbard KB and Hepler JR. 2006. Cell signalling diversity of the Gq[alpha] family of heterotrimeric G proteins. Cellular Signalling 18:135-150 https://doi.org/10.1016/j.cellsig.2005.08.004
  56. Imai A, Takagi A, Horibe S, Takagi Hand Tamaya T. 1998a. Evidence for tight coupling of gonadotropin-releasing hormone receptor to stimulated Fas ligand expression in reproductive tract tumors: Possible Mechanism for Hormonal Control of Apoptotic Cell Death. J. Clin. Endocrinol. Metab. 83:427-431 https://doi.org/10.1210/jc.83.2.427
  57. Imai A, Takagi A, Horibe S, Takagi Hand Tamaya T. 1998b. Fas and Fas ligand system may mediate antiproliferative activity of gonadotropin-releasing hormone receptor in endometrial cancer cells. Int. J. Oncol. 13:97-100
  58. Imai A, Takagi H, Horibe S, Fuseya T and Tamaya T. 1996. Coupling of gonadotropin-releasing hormone receptor to Gi protein in human reproductive tract tumors. J. Clin. Endocrinol. Metab. 81:3249-3253 https://doi.org/10.1210/jc.81.9.3249
  59. Irmer G, Burger C, Muller R, Ortmann O, Peter U, Kakar SS, Neill JD, Schulz KD and Emons G. 1995. Expression of the messenger RNAs for luteinizing hormone-releasing hormone (LHRH) and its receptor in human ovarian epithelial carcinoma. Cancer Res. 55:817-822
  60. Islami D, Chardonnens D, Campana A and Bischof P. 2001. Comparison of the effects of GnRH- I and GnRH- II on HCG synthesis and secretion by first trimester trophoblast. Mol. Hum. Reprod. 7:3-9 https://doi.org/10.1093/molehr/7.1.3
  61. Iwashita M, Evans MI and Catt KJ. 1986. Characterization of a gonadotropin-releasing hormone receptor site in term placenta and chorionic villi. J. Clin. Endocrinol. Metab. 62: 127-133 https://doi.org/10.1210/jcem-62-1-127
  62. Jiang Y, Ma W, Wan Y, Kozasa T, Hattori S and Huang XY. 1998. The G protein G alpha12 stimulates Bruton's tyrosine kinase and a rasGAP through a conserved PH/BM domain. Nature 395:808-813 https://doi.org/10.1038/27454
  63. Johnson GL and Lapadat R. 2002. Mitogen-Activated Protein Kinase Pathways Mediated by ERK, JNK, and p38 Protein Kinases. Science 298:1911-1912 https://doi.org/10.1126/science.1072682
  64. Johnson MS, Wolbers WB, Noble J, Fennell M and Mitchell R. 1995. Effect of tyrosine kinase inhibitors on luteinizing hormone-releasing hormone (LHRH)-induced gonadotropin release from the anterior pituitary. Mol. Cell Endocrinol. 109:69-75 https://doi.org/10.1016/0303-7207(95)03484-O
  65. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW and Burgess AW. 2003. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp. Cell. Res. 284: 31-53 https://doi.org/10.1016/S0014-4827(02)00098-8
  66. Kakar SS, Musgrove LC, Devor DC, Sellers JC and Neill JD. 1992. Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor. Biochem. Biophys. Res. Commun. 189:289-295 https://doi.org/10.1016/0006-291X(92)91556-6
  67. Kang SK, Cheng KW, Nathwani PS, Choi KC and Leung PC. 2000a. Autocrine role of gonadotropin-releasing hormone and its receptor in ovarian cancer cell growth. Endocrine 13:297-304 https://doi.org/10.1385/ENDO:13:3:297
  68. Kang SK, Tai C-J, Cheng KW and Leung PCK. 2000b. Gonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cells. Molecularand Cellular Endocrinology 170:143-151 https://doi.org/10.1016/S0303-7207(00)00320-8
  69. Kang SK, Tai C-J, Nathwani PS, Choi K-C and Leung PCK. 2001. Stimulation of mitogen-activated protein kinase by gonadotropin-releasing hormone in human granulosa-luteal cells. Endocrinology 142:671-679 https://doi.org/10.1210/en.142.2.671
  70. Kennedy N and Davis R. 2003. Role of JNK in tumor development. Cell Cycle 2:199-201
  71. Kim JH, Park DC, Kim JW, Choi YK, Lew YO, Kim DH, Jung JK, Lim YA and Namkoong SE. 1999. Antitumor effect of GnRH agonist in epithelial ovarian cancer. Gynecologic Oncology 74:170-180 https://doi.org/10.1006/gyno.1999.5413
  72. Kim K-Y, Choi K-C, Park S-H, Chou C-S, Auersperg N and Leung PCK. 2004. Type II Gonadotropin-releasing hormone stimulates p38 mitogen-activated protein kinase and apoptosis in ovarian cancer cells. J. Clin. Endocrinol. Metab. 89:3020-3026 https://doi.org/10.1210/jc.2003-031871
  73. Kimura A, Ohmichi M, Kurachi H, Ikegami H, Hayakawa J, Tasaka K, Kanda Y, Nishio Y, Jikihara H, Matsuura N and Murata Y. 1999. 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. Cancer Res. 59:5133-5142
  74. Klapper LN, Kirschbaum MH, Sela M and Yarden Y. 2000. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv. Cancer. Res 77:25-79 https://doi.org/10.1016/S0065-230X(08)60784-8
  75. KleinmanD, Douvdevani A, Schally A, Levy J and Sharoni Y. 1994. Direct growth inhibition of human endometrial cancer cells by the gonadotropin-releasing hormone antagonist SB-75: role of apoptosis. Am. J. Obstet. Gynecol. 170:96-102 https://doi.org/10.1016/S0002-9378(94)70391-4
  76. Kraus S, Naor Z and Seger R. 2001. Intracellular signaling pathways mediated by the Gonadotropin-Releasing Hormone (GnRH) receptor. Arch. Med. Res. 32:499-509 https://doi.org/10.1016/S0188-4409(01)00331-9
  77. Kraus S, Naor Z and Seger R. 2006. Gonadotropin-releasing hormone in apoptosis of prostate cancer cells. Cancer Lett. 234:109-123 https://doi.org/10.1016/j.canlet.2005.02.038
  78. Kuhn B and Gudermann T. 1999. The luteinizing hormone receptor activates phospholipase C via preferential coupling to $G{i2}$. Biochemistry 38:12490-12498 https://doi.org/10.1021/bi990755m
  79. Lee M, Liebow C, Kamer A and Schally A. 1991. Effects of epidermal growth factor and analogues of luteinizing hormone-releasing hormone and somatostatin on phosphorylation and dephosphorylation of tyrosine residues of specific protein substrates in various tumors. Proc. Natl. Acad. Sci. USA 88:1656-1660 https://doi.org/10.1073/pnas.88.5.1656
  80. Levi NL, Hanoch T, Benard O, Rozenblat M, Harris D, Reiss N, Naor Z and Seger R. 1998. Stimulation of Jun N-terminal Kinase (JNK) by gonadotropin-releasing hormone in pituitary {alpha}T3-1 cell line is mediated by protein kinase C, c-Src, and CDC42. Mol. Endocrinol. 12:815-824 https://doi.org/10.1210/me.12.6.815
  81. Lin A. 2003. Activation of the JNK signaling pathway: breaking the brake on apoptosis. Bioessays 25:17-24 https://doi.org/10.1002/bies.10204
  82. Lin X, Voyno-Yasenetskaya TA, Hooley R, Lin CY, Orlowski J and Barber DL. 1999. Galpha12 differentially regulates $Na^{+}$-$H^{+}$ exchanger isoforms. J. BioI. Chem. 271:22604-22610
  83. Liu F, Austin DA, Mellon PL, Olefsky JM and Webster NJG. 2002. GnRH activates ERK1/2 leading to the induction of c-fos and LH{beta} protein expression in L{beta}T2 cells. Mol. Endocrinol. 16:419-434 https://doi.org/10.1210/me.16.3.419
  84. Maihle NJ, Baron AT, Barrette BA, Boardman CH, Christensen TA, Cora EM, Faupel-Badger JM, Greenwood T, Juneja SC, Lafky JM, Lee H, Reiter JL and Podratz KC. 2002. EGF/ErbB receptor family in ovarian cancer. Cancer Treat. Res. 107:247-258
  85. Mansour S, Matten W, Hermann A, Candia J, Rong S, Fukasawa K, Vande Woude G and Ahn N. 1994. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265:966-970 https://doi.org/10.1126/science.8052857
  86. Matsuo H, Baba Y, Nair RM, Arimura A and Schally AV. 1971. Structure of the porcine LH- and FSH-releasing hormone. I. The proposed amino acid sequence. Biochem. Biophys. Res. Commun. 43:1334-1339 https://doi.org/10.1016/S0006-291X(71)80019-0
  87. Mehmet H. 2000. Caspases find a new place to hide. Nature 403:29-30 https://doi.org/10.1038/47377
  88. Millar R, Conklin D, Lofton-Day C, Hutchinson E, Troskie B, Illing N, Sealfon S and Hapgood J. 1999. A novel human GnRH receptor homolog gene: abundant and wide tissue distribution of the antisense transcript. J. Endocrinol. 162: 117-126 https://doi.org/10.1677/joe.0.1620117
  89. Millar R, 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 and Katz A. 2001. A novel mammalian receptor for the evolutionarily conserved type II GnRH. Proc. Natl. Acad. Sci. USA 98:9636-9641 https://doi.org/10.1073/pnas.141048498
  90. Millar RP, Lu Z-L, Pawson AJ, Flanagan CA, Morgan K and Maudsley SR. 2004. Gonadotropin-releasing hormone receptors. Endocr. Rev. 25:235-275 https://doi.org/10.1210/er.2003-0002
  91. Miller WR, Scott WN, Morris R, Fraser HM and Sharpe RM. 1985. Growth of human breast cancer cells inhibited by a luteinizing hormone-releasing hormone agonist. Nature 313: 231-233 https://doi.org/10.1038/313231a0
  92. Minn AJ, Swain RE, Ma A and Thompson CB. 1998. Recent progress on the regulation of apoptosis by Bcl-2 family members. Adv. Immunol. 70:245-279 https://doi.org/10.1016/S0065-2776(08)60388-0
  93. Morgan K, Conklin D, Pawson AJ, Sellar R, Ott TR and Millar RP. 2003. A transcriptionally active human type II gonadotropin-releasing hormone receptor gene homologoverlaps two genes in the antisense orientation on chromosome lq.12. Endocrinology 144:423-436 https://doi.org/10.1210/en.2002-220622
  94. Motomura S. 1998. Induction of apoptosis in ovarian carcinoma cell line by gonadotropin-releasing hormone agonist. Kurume. Med. J. 45:27-32 https://doi.org/10.2739/kurumemedj.45.27
  95. Nagao M, Kaziro Y and Itoh H. 1999. The Src family tyrosine kinase is involved in Rho-dependent activation of c-Jun N-terminal kinase by G12. Oncogene 18:4425-4434 https://doi.org/10.1038/sj.onc.1202832
  96. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA and Yuan J. 2000. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403:98-103 https://doi.org/10.1038/47513
  97. Naor Z, Benard O and Seger R. 2000. Activation of MAPK cascades by G-protein-coupled receptors: The case of gonadotropin-releasing hormone receptor. Trends Endocrinol. Metab. 11:91-99 https://doi.org/10.1016/S1043-2760(99)00232-5
  98. Naor Z, Clayton RN and Catt KJ. 1980. Characterization of gonadotropin-releasing hormone receptors in cultured rat pituitary cells. Endocrinology 107:1144-1152 https://doi.org/10.1210/endo-107-4-1144
  99. Naor Z. 1990. Signal transduction mechanisms of $Ca^{2+}$ mobilizing hormones: the case of gonadotropin-releasing hormone. Endocr. Rev. 11:326-353 https://doi.org/10.1210/edrv-11-2-326
  100. Negri E, Pelucchi C, Franceschi S, Montella M, Conti E, Dal Maso L, Parazzini F, Tavani A, Carbone A and La Vecchia C. 2003. Family history of cancer and risk of ovarian cancer. Eur. J. Cancer. 39:505-510 https://doi.org/10.1016/S0959-8049(02)00743-8
  101. Neill JD, Duck LW, Sellers JC and Musgrove LC. 2001. A Gonadotropin-Releasing Hormone (GnRH) receptor specific for GnRH II in primates. Biochem. Biophys. Res. Commun. 282:1012-1018 https://doi.org/10.1006/bbrc.2001.4678
  102. Neill JD. 2002. Minireview: GnRH and GnRH receptor genes in the human genome. Endocrinology 143:737-743 https://doi.org/10.1210/en.143.3.737
  103. Pahwa GS, Vollmer G, Knuppen Rand Emons G. 1989. Photoaffinity labelling of gonadotropin releasing hormone binding sites in human epithelial ovarian carcinomata. Biochem. Biophys. Res. Commun. 161:1086-1092 https://doi.org/10.1016/0006-291X(89)91354-5
  104. Pal D, Miller BT and Parkening TA. 1992. Topographical mapping of GnRH receptors on dispersed mouse pituitary cells by backscattered electron imaging. Anat. Rec. 233:89-96 https://doi.org/10.1002/ar.1092330112
  105. Pawson AJ, Maudsley S, Morgan K, Davidson L, Naor Z and Millar RP. 2005. Inhibition of human type i gonadotropin-releasing hormone receptor (GnRHR) function by expression of a human type II GnRHR gene fragment. Endocrinology 146:2639-2949 https://doi.org/10.1210/en.2005-0133
  106. Purdie DM, Bain CJ, Siskind V, Webb PM and Green AC. 2003. Ovulation and risk of epithelial ovarian cancer. Int. J. Cancer 104:228-232 https://doi.org/10.1002/ijc.10927
  107. Qayum A, Gullick W, Clayton RC, Sikora K and Waxman J. 1990. The effects of gonadotrophin releasing hormone analogues in prostate cancer are mediated through specific tumour receptors. Br. J. Cancer 62:96-99
  108. Raingeaud J, Gupta S, Dickens M and Han J. 1995. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. BioI. Chem. 270:7420-7426 https://doi.org/10.1074/jbc.270.13.7420
  109. Raingeaud J, Whitmarsh A, Barrett T, Derijard B and Davis R. 1996. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen- activated protein kinase signal transduction pathway. Mol. Cell. BioI. 16:1247-1255
  110. Reinhart J, Mertz LM and Catt KJ. 1992. Molecular cloning and expression of cDNA encoding the murine gonadotropin-releasing hormone receptor. J. BioI. Chem. 267:21281-21284
  111. Reiss N, Llevi LN, Shacham S, Harris D, Seger Rand Naor Z. 1997. Mechanism of mitogen-activated protein kinase activation by gonadotropin-releasing hormone in the pituitary a T3-1 cell line: Differential roles of calcium and protein kinase C. Endocrinology 138:1673-1682 https://doi.org/10.1210/en.138.4.1673
  112. Risch HA. 1998. Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. JNCI Cancer Spectrum 90:1774-1786 https://doi.org/10.1093/jnci/91.7.650
  113. Roberson M, Misra-Press A, Laurance M, Stork P and Maurer R. 1995. A role for mitogen-activated protein kinase in mediating activation of the glycoprotein hormone alpha-subunit promoter by gonadotropin-releasing hormone. Mol. Cell. Biol. 15:3531-3539
  114. Roberson MS, Zhang T, Li HL and Mulvaney JM. 1999. Activation of the p38 mitogen-activated protein kinase pathway by gonadotropin-releasing hormone. Endocrinology 140: 1310-1318 https://doi.org/10.1210/en.140.3.1310
  115. Robinson MJ and Cobb MH. 1997. Mitogen-activated protein kinase pathways. Curr. Opin. Cell. Biol. 9:180-186 https://doi.org/10.1016/S0955-0674(97)80061-0
  116. Rose A, Froment P, Perrot V, Quon MJ, LeRoith D and Dupont J. 2004. The luteinizing hormone-releasing hormone inhibits the anti-apoptotic activity of insulin-like growth factor-l in pituitary aiphaT3 cells by protein kinase Calpha-mediated negative regulation of Akt. J. BioI. Chem. 279:52500-52516
  117. Rzepka-Gorska I, Chudecka-Glaz A, Kosmider M and Malecha J. 2003. GnRH analogues as an adjuvant therapy for ovarian cancer patients. Int. J. Gynaecol. Obstet. 81:199-205 https://doi.org/10.1016/S0020-7292(03)00029-8
  118. Salomon DS, Brandt R, Ciardiello F and Normanna N. 1995. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit. Rev. Oncol. Hematol. 19: 183-232 https://doi.org/10.1016/1040-8428(94)00144-I
  119. Salvesen GS and Dixit VM. 1997. Caspases: intracellular signaling by proteolysis. Cell 91:443-446 https://doi.org/10.1016/S0092-8674(00)80430-4
  120. Santen R, Manni A, Harvey H and Redmond C. 1990. Endocrine treatment of breast cancer in women. Endocr. Rev. 11:221-265 https://doi.org/10.1210/edrv-11-2-221
  121. Savino L, Baldini B, Susini T, Pulli F, Antignani L and Massi GB. 1992. GnRH analogs in gynecological oncology: a review. J. Chemother. 4:312-320
  122. Schally AV, Comaru-Schally AM, Nagy A, Kovacs M, Szepeshazi K, Plonowski A, Varga JL and Halmos G. 2001. Hypothalamic hormones and cancer. Front. Neuroendocrinol. 22:248-291 https://doi.org/10.1006/frne.2001.0217
  123. Schally AV. 1999. Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis. Peptides 20:1247-1262 https://doi.org/10.1016/S0196-9781(99)00130-8
  124. Schulz RW, Bosma PT, Zandbergen MA, Van der Sanden MC, Van Dijk W, Peute J, Bogerd J and Goos HJ. 1993. Two gonadotropin-releasing hormones in the African catfish, Clarias gariepinus: localization, pituitary receptor binding, and gonadotropin release activity. Endocrinology 133: 1569-1577 https://doi.org/10.1210/en.133.4.1569
  125. Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S and Peter ME. 1998. Apoptosis signaling by death receptors. Eur. J. Biochem. 254:439-459 https://doi.org/10.1046/j.1432-1327.1998.2540439.x
  126. Sealfon SC, Weinstein H and Millar RP. 1997. Molecular mechanisms of ligand interaction with the gonadotropin-releasing hormone receptor. Endocr. Rev. 18:180-205 https://doi.org/10.1210/er.18.2.180
  127. Shacham S, Harris D, Ben-Shlomo H, Cohen I, Bonfil D, Przedecki F, Lewy H, Ashkenazi IE, Seger Rand Naor Z. 2001. Mechanism of GnRH receptor signaling on gonadotropin release and gene expression in pituitary gonadotrophs. Vitam. Horm. 63:63-90 https://doi.org/10.1016/S0083-6729(01)63003-6
  128. Shah BH, Farshori MP, Jambusaria A and Catt KJ. 2003. Roles of Src and epidermal growth factor receptor transactivation in transient and sustained ERK1/2 responses to gonadotropin-releasing hormone receptor activation. J. Biol, Chem. 278:19118-19126 https://doi.org/10.1074/jbc.M212932200
  129. Sharp PJ, Talbot RT, Main GM, Dunn IC, Fraser HM and Huskisson NS. 1990. Physiological roles of chicken LHRH-I and -II in the control of gonadotrophin release in the domestic chicken. J. Endocrinol. 124:291-299 https://doi.org/10.1677/joe.0.1240291
  130. Sherwood NM, Lovejoy DA and Coe IR. 1993. Origin of mammalian gonadotropin-releasing hormones. Endocr. Rev. 14: 241-54 https://doi.org/10.1210/edrv-14-2-241
  131. Shoham Z. 1994. Epidemiology, etiology, and fertility drugs in ovarian epithelial carcinoma: where are we today? Fertil. Steril. 62:433-448
  132. Stojilkovic SS, Tomic M, Kukuljan M and Catt KJ. 1994. Control of calcium spiking frequency in pituitary gonadotrophs by a single-pool cytoplasmic oscillator. Mol. Pharmacol. 45:1013-1021
  133. Sun YM, Flanagan CA, Illing N, Ott TR, Sellar R, Fromme BJ, Hapgood J, Sharp P, Sealfon SC and Millar RP. 2001. A chicken gonadotropin-releasing hormone receptor that confers agonist activity to mammalian antagonists. Identification of D-Lys(6) in the ligand and extracellular loop two of the receptor as determinants. J. Biol. Chem. 276: 7754-7761 https://doi.org/10.1074/jbc.M009020200
  134. Sundaresan S, Colin IM, Pestell RG and Jameson JL. 1996. Stimulation of mitogen-activated protein kinase by gonadotropin-releasing hormone: evidence for the involvement of protein kinase C. Endocrinology 137:304-311 https://doi.org/10.1210/en.137.1.304
  135. Tanaka T, Kohno T, Kinoshita S, Mukai H, Itoh H, Ohya M, Miyazawa T, Higashijima T and Wakamatsu K. 1998. Alpha helix content of G protein alpha subunit is decreased upon activation by receptor mimetics. J. Biol. Chem. 273:3247-3252 https://doi.org/10.1074/jbc.273.6.3247
  136. Thompson C. 1995. Apoptosis in the pathogenesis and treatment of disease. Science 267:1456-1462 https://doi.org/10.1126/science.7878464
  137. Tse FW, Tse A, Hille B, Horstmann Hand Almers W. 1997. Local $Ca^{2+}$ release from internal stores controls exocytosis in pituitary gonadotrophs. Neuron 18:121-132 https://doi.org/10.1016/S0896-6273(01)80051-9
  138. Tsutsumi M, Zhou W, Millar RP, Mellon PL, Roberts JL, Flanagan CA, Dong K, Gillo B and Sealfon SC. 1992. Cloning and functional expression of a mouse gonadotropin-releasing hormone receptor. Mol. Endocrinol. 6: 1163-1169 https://doi.org/10.1210/me.6.7.1163
  139. van Dam H, Wilhelm D, Herr I, Steffen A, Herrlich P and Angel P. 1995. ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. EMBO 14:1798-1811
  140. Verheij M, Bose R, Lin XH, Yao B, Jarvis WD, Grant S, Birrer MJ, Szabo E, Zon LI, Kyriakis JM, Haimovitz-Friedman A, Fuks Z and Kolesnick RN. 1996. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 380:75-79 https://doi.org/10.1038/380075a0
  141. Wang L, Bogerd J, Choi HS, Seong JY, Soh JM, Chun SY, Blomenrohr M, Troskie BE, Millar RP, Yu WH, McCann SM and Kwon HB. 2001. Three distinct types of GnRH receptor characterized in the bullfrog. Proc. Natl. Acad. Sci. USA 98:361-366 https://doi.org/10.1073/pnas.011508498
  142. Wang Y, Matsuo H, Kurachi O and Maruo T. 2002. Down-regulation of proliferation and up-regulation of apoptosis by gonadotropin-releasing hormone agonist in cultured uterine leiomyoma cells. Eur. J. Endocrinol. 146:447-456 https://doi.org/10.1530/eje.0.1460447
  143. Wasylyk B, Hagman J and Gutierrez-Hartmann A. 1998. Ets transcription factors: nuclear effectors of the Ras-MAP-kinase signaling pathway. Trends Biochem. Sci. 23:213-216 https://doi.org/10.1016/S0968-0004(98)01211-0
  144. Weil C, Crim LW, Wilson CE and Cauty C. 1992. Evidence of GnRH receptors in cultured pituitary cells of the winter flounder (Pseudopleuronectes americanus W.). Gen. Compo Endocrinol. 85: 156-164 https://doi.org/10.1016/0016-6480(92)90183-K
  145. Wells A. 1999. EGF receptor. Int. J. Biochem. Cell BioI. 31: 637-643 https://doi.org/10.1016/S1357-2725(99)00015-1
  146. White RB, Eisen JA, Kasten TL and Fernald RD. 1998. Second gene for gonadotropin-releasing hormone in humans. Proc. Natl. Acad. Sci. USA 95:305-309 https://doi.org/10.1073/pnas.95.1.305
  147. Whitmarsh AJ, Shore P, Sharrocks AD and Davis RJ. 1995. Integration of MAP kinase signal transduction pathways at the serum response element. Science 269:403-407 https://doi.org/10.1126/science.7618106
  148. Wormald PJ, Eidne KA and Millar RP. 1985. Gonadotropin-releasing hormone receptors in human pituitary: ligand structural requirements, molecular size, and cationic effects. J. Clin. Endocrinol. Metab. 61:1190-1194 https://doi.org/10.1210/jcem-61-6-1190
  149. Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME. 1995. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326-1331 https://doi.org/10.1126/science.270.5240.1326
  150. Yarden Y and Sliwkowski MX. 2001. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2:127-37 https://doi.org/10.1038/35052073
  151. Yen A, Roberson M, Varvayanis S and Lee A. 1998. Retinoic acid induced mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase-dependent MAP kinase activation needed to elicit HL-60 cell differentiation and growth arrest. Cancer Res. 58:3163-3172
  152. Zheng L, Stojilkovic SS, Hunyady L, Krsmanovic LZ and Cart KJ. 1994. Sequential activation of phospholipase-C and -D in agonist-stimulated gonadotrophs. Endocrinology 134:1446-1454 https://doi.org/10.1210/en.134.3.1446
  153. Zhu X and Birnbaumer L. 1996. G protein subunits and the stimulation of phospholipase C by Gs- and Gi-coupled receptors: Lack of receptor selectivity of Galpha 16 and evidence for a synergic interaction between Gbeta gamma and the alpha subunit of a receptor-activated G protein. Proc. Natl. Acad. Sci. USA 93:2827-2831 https://doi.org/10.1073/pnas.93.7.2827
  154. Zidan J, Zohar S, Mijiritzky I, Kral S and Bilenca B. 2002. Treating relapsed epithelial ovarian cancer with luteinizing hormone-releasing agonist (goserelin) after failure of chemotherapy. Isr. Med. Assoc. J. 4:597-599