Top

Reviews in Endocrine and Metabolic Disorders

07-11-2024 | Prostate Cancer

GHRH and the prostate

Authors: Laura Muñoz-Moreno, Irene D. Román, Ana M. Bajo

Published in: Reviews in Endocrine and Metabolic Disorders

Abstract

In the late 1960s and early 1970s, hypothalamic regulatory hormones were isolated, characterized and sequenced. Later, it was demonstrated hypothalamic and ectopic production of growth hormone-releasing hormone (GHRH) in normal and tumor tissues, of both humans and animals. Pituitary-type GHRH receptors (pGHRH-R) had been demonstrated to be expressed predominantly in the anterior pituitary gland but also found in other somatic cells, and significantly present in various human cancers; in addition, the expression of splice variants (SVs) of GHRH receptor (GHRH-R) has been found not only in the pituitary but in extrapituitary tissues, including human neoplasms. In relation to the prostate, besides the pGHRH-R, it has been detected the presence of truncated splice variants of GHRH-R (SV1-SV4) in normal human prostate and human prostate cancer (PCa) specimens; lastly, a novel SV of GHRH-R has been detected in human PCa. Signaling pathways activated by GHRH include AC/cAMP/PKA, Ras/Raf/ERK, PI3K/Akt/mTOR and JAK2/STAT3, which are involved in processes such as cell survival, proliferation and cytokine secretion. The neuropeptide GHRH can also transactivate the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER)-2. Thus, GHRH-Rs have become drug targets for several types of clinical conditions, including prostate-related conditions such as prostatitis, benign hyperplasia and cancer. Over the last fifty years, the development of GHRH-R receptor antagonists has been unstoppable, improving their potency, stability and affinity for the receptor. The last series of GHRH-R antagonists, AVR, exhibits superior anticancer and anti-inflammatory activities in both in vivo and in vitro assays.

Reichlin S. Growth hormone content of pituitaries from rats with hypothalamic lesions. Endocrinology. 1961;69:225–30. https://doi.org/10.1210/endo-69-2-225.CrossRefPubMed

Schally AV, Steelman SL, Bowers CY. Effect of hypothalamic extracts on release of growth hormone in vitro. Proc Soc Exp Biol Med. 1965;119(1):208–12. https://doi.org/10.3181/00379727-119-30138.CrossRefPubMed

Krulich L, Dhariwal AP, McCann SM. Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro. Endocrinology. 1968;83(4):783–90. https://doi.org/10.1210/endo-83-4-783.CrossRefPubMed

Frohman LA, Szabo M. Ectopic production of growth hormone-releasing factor by carcinoid and pancreatic islet tumors associated with acromegaly. Prog Clin Biol Res. 1981;74:259–71.PubMed

Guillemin R, Brazeau P, Böhlen P, Esch F, Ling N, Wehrenberg WB. Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982;218(4572):585–7. https://doi.org/10.1126/science.6812220.CrossRefPubMed

Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature. 1982;300(5889):276–8. https://doi.org/10.1038/300276a0.CrossRefPubMed

Frohman LA, Kineman RD. Growth hormone-releasing hormone and pituitary somatotrope proliferation. Minerva Endocrinol. 2002;27(4):277–85.PubMed

Kiaris H, Schally AV, Kalofoutis A. Extrapituitary effects of the growth hormone-releasing hormone. Vitam Horm. 2005;70:1–24. https://doi.org/10.1016/S0083-6729(05)70001-7.CrossRefPubMed

Frohman LA, Downs TR, Chomczynski P, Brar A, Kashio Y. Regulation of growth hormone-releasing hormone gene expression and biosynthesis. Yale J Biol Med. 1989;62(5):427–33.PubMedPubMedCentral

10.

Ling N, Esch F, Böhlen P, Brazeau P, Wehrenberg WB, Guillemin R. Isolation, primary structure, and synthesis of human hypothalamic somatocrinin: growth hormone-releasing factor. Proc Natl Acad Sci U S A. 1984;81(14):4302–6. https://doi.org/10.1073/pnas.81.14.4302.CrossRefPubMedPubMedCentral

11.

Posner SF, Vaslet CA, Jurofcik M, Lee A, Seidah NG, Nillni EA. Stepwise posttranslational processing of progrowth hormone-releasing hormone (proGHRH) polypeptide by furin and PC1. Endocrine. 2004;23(2–3):199–213. https://doi.org/10.1385/ENDO:23:2-3:199.CrossRefPubMed

12.

Zhou F, Zhang H, Cong Z, Zhao LH, Zhou Q, Mao C, Cheng X, Shen DD, Cai X, Ma C, Wang Y, Dai A, Zhou Y, Sun W, Zhao F, Zhao S, Jiang H, Jiang Y, Yang D, Eric XuH, Zhang Y, Wang MW. Structural basis for activation of the growth hormone-releasing hormone receptor. Nat Commun. 2020;11(1):5205. https://doi.org/10.1038/s41467-020-18945-0.CrossRefPubMedPubMedCentral

13.

Pezzolo A, Gimelli G, Sposito M, Giussani U, Rossi E, Zuffardi O. Definitive assignment of the growth hormone-releasing factor gene to 20q11.2. Hum Genet. 1994;93:213–4. https://doi.org/10.1007/BF00210616.CrossRefPubMed

14.

Mutsuga N, Iwasaki Y, Morishita M, Nomura A, Yamamori E, Yoshida M, Asai M, Ozaki N, Kambe F, Seo H, Oiso Y, Saito H. Homeobox protein Gsh-1- dependent regulator of the rat GHRH gene promoter. Mol Endocrinol. 2001;15:2149–56. https://doi.org/10.1210/mend.15.12.0747.CrossRefPubMed

15.

Barabutis N, Schally AV. Growth hormone-releasing hormone: extrapituitary effects in physiology and pathology. Cell Cycle. 2010;9:4110–6. https://doi.org/10.4161/cc.9.20.13787.CrossRefPubMed

16.

Frohman LA, Nernardis LL, Kant KJ. Hypothalamic stimulation of growth hormone secretion. Science. 1968;162:580–2. https://doi.org/10.1126/science.162.3853.580.CrossRefPubMed

17.

Bagnato A, Moretti C, Ohnishi J, Frajese G, Catt KJ. Expression of the growth hormone-releasing hormone gene and its peptide product in the rat ovary. Endocrinology. 1992;130(3):1097–102. https://doi.org/10.1210/endo.130.3.1537276.CrossRefPubMed

18.

Berry SA, Srivastava CH, Rubin LR, Phipps WR, Pescovitz OH. Growth hormone-releasing hormone-like messenger ribonucleic acid and immunoreactive peptide are present in human testis and placenta. J Clin Endocrinol Metab. 1992;75(1):281–4. https://doi.org/10.1210/jcem.75.1.1619020.CrossRefPubMed

19.

Bosman FT, de la Riviere AB, Giard RW, Verhofstad AA, Cramer-Knijnenburg G. Amine and peptide hormone production by lung carcinoid: a clinicopathological and immunocytochemical study. J Clin Pathol. 1984;37(8):931–6. https://doi.org/10.1136/jcp.37.8.931.CrossRefPubMedPubMedCentral

20.

Khorram O, Garthwaite M, Grosen E, Golos T. Human uterine and ovarian expression of growth hormone-releasing hormone messenger RNA in benign and malignant gynecologic conditions. Fertil Steril. 2001;75:174–9. https://doi.org/10.1016/S0015-0282(00)01658-7.CrossRefPubMed

21.

Moretti C, Mencacci C, Frajese GV, Cerilli M, Frajese G. Growth hormone-releasing hormone and pituitary adenylate cyclase-activating polypeptide in the reproductive system. Trends Endocrinol Metab. 2002;13:428–35. https://doi.org/10.1016/S1043-2760(02)00632-X. CrossRefPubMed

22.

Ciampani T, Fabbri A, Isidori A, Dufau ML. Growthhormone-releasing hormone is produced by rat Leydigcell in culture and acts as a positive regulator of Leydigcell function. Endocrinology. 1992;131:2785–92. https://doi.org/10.1210/endo.131.6.1332849.CrossRefPubMed

23.

Matsubara S, Sato M, Mizobuchi M, Niimi M, Takahara J. Differential gene expression of growth hormone (GH)-releasing hormone (GRH) and GRHreceptor in various rat tissues. Endocrinology. 1995;136:4147–50. https://doi.org/10.1210/endo.136.9.7649123.CrossRefPubMed

24.

Kiaris H, Koutsilieris M, Kalofoutis A, Schally AV. Growth hormone-releasing hormone and extrapituitary tumorigenesis: therapeutic and diagnostic applica-tions of growth hormone-releasing hormone antagonists. Expert Opin Investig Drugs. 2003;12:1385–94. https://doi.org/10.1517/13543784.12.8.1385.CrossRefPubMed

25.

Mayo KE, Miller TL, DeAlmeida V, Zheng J, Godfrey PA. The growth-hormone-releasing hormone receptor: signal transduction, gene expression, and physiological function in growth regulation. Ann N Y Acad Sci. 1996;805:184–203. https://doi.org/10.1111/j.1749-6632.1996.tb17483.x.CrossRefPubMed

26.

Shibasaki T, Kiyosawa Y, Masuda A, Nakahara M, Imaki T, Wakabayashi I, Demura H, Shizume K, Ling N. Distribution of growth hormone-releasing hormone-like immunoreactivity in human tissue extracts. J Clin Endocrinol Metab. 1984;59(2):263–8. https://doi.org/10.1210/jcem-59-2-263.CrossRefPubMed

27.

Stephanou A, Knight RA, Lightman SL. Production of a growth hormone-releasing hormone-like peptide and its mRNA by human lymphocytes. Neuroendocrinology. 1991;53(6):628–33.PubMed

28.

Wu HM, Schally AV, Cheng JC, Zarandi M, Varga J, Leung PC. Growth hormone-releasing hormone antagonist induces apoptosis of human endometrial cancer cells through PKCδ-mediated activation of p53/p21. Cancer Lett. 2010;298(1):16–25. https://doi.org/10.1016/j.canlet.2010.05.022.CrossRefPubMed

29.

Barabutis N, Siejka A, Schally AV. Effects of growth hormone-releasing hormone and its agonistic and antagonistic analogs in cancer and non-cancerous cell lines. Int J Oncol. 2010;36(5):1285–9. https://doi.org/10.3892/ijo_00000613.CrossRefPubMed

30.

Havt A, Schally AV, Halmos G, Varga JL, Toller GL, Horvath JE, Szepeshazi K, Köster F, Kovitz K, Groot K, Zarandi M, Kanashiro CA. The expression of the pituitary growth hormone-releasing hormone receptor and its splice variants in normal and neoplastic human tissues. Proc Natl Acad Sci USA. 2005;102:17424–9. https://doi.org/10.1073/pnas.0506844102.CrossRefPubMedPubMedCentral

31.

Kiaris H, Schally AV, Varga JL. Antagonists of growth hormone-releasing hormone inhibit the growth of U-87MG human glioblastoma in nude mice. Neoplasia. 2000;2(3):242–50. https://doi.org/10.1038/sj.neo.7900074.CrossRefPubMedPubMedCentral

32.

Ziegler CG, Brown JW, Schally AV, Erler A, Gebauer L, Treszl A, Young L, Fishman LM, Engel JB, Willenberg HS, Petersenn S, Eisenhofer G, Ehrhart-Bornstein M, Bornstein SR. Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: antiproliferative effects of peptide analogues. Proc Natl Acad Sci U S A. 2009;106(37):15879–84. https://doi.org/10.1016/j.canlet.2010.05.022.CrossRefPubMedPubMedCentral

33.

Theophanous E, Petraki C, Scorilas A, Komborozos V, Veloudis G, Varga JL, Zarandi M, Schally AV, Koutsilieris M. The immunohistochemical expression of growth hormone-releasing hormone receptor splice variant 1 is a favorable prognostic marker in colorectal cancer. Mol Med. 2009;15(7–8):242–7. https://doi.org/10.2119/molmed.2008.00132.CrossRefPubMedPubMedCentral

34.

Devesa J. The Complex world of regulation of pituitary growth hormone secretion: the role of ghrelin, klotho, and nesfatins in it. Front Endocrinol (Lausanne). 2021;12: 636403. https://doi.org/10.3389/fendo.2021.636403.CrossRefPubMed

35.

Olarescu NC, Gunawardane K, Hansen TK, et al. Normal physiology of growth hormone in adults. 2019 Oct 16. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. http://www.ncbi.nlm.nih.gov/books/nbk279056/.

36.

Vélez EJ, Unniappan S. A comparative update on the neuroendocrine regulation of growth hormone in vertebrates. Front Endocrinol. 2021;11: 614981. https://doi.org/10.3389/fendo.2020.614981.CrossRef

37.

Granata R. Peripheral activities of growth hormone-releasing hormone. J Endocrinol Invest. 2016;39(7):721–7. https://doi.org/10.1007/s40618-016-0440-x.CrossRefPubMed

38.

Zhang M, Chen T, Lu X, Lan X, Chen Z, Lu S. G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery. Signal Transduct Target Ther. 2024;9(1):88. https://doi.org/10.1038/s41392-024-01803-6.CrossRefPubMedPubMedCentral

39.

Hauser A, Attwood M, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drugdiscovery: new agents, targets and indications. Nat Rev DrugDiscov. 2017;16:829–42. https://doi.org/10.1038/nrd.2017.178.CrossRef

40.

Lagerstrom MC, Schiöth HB. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov. 2008;7(4):339–57. https://doi.org/10.1038/nrd2518.CrossRefPubMed

41.

Whalen EJ, Rajagopal S, Lefkowitz RJ. Therapeutic potential of β-arrestin- and G protein-biased agonists. Trends Mol Med. 2011;17(3):126–39. https://doi.org/10.1016/j.molmed.2010.11.004.CrossRefPubMed

42.

Ericksen SS, Cummings DF, Weinstein H, Schetz JA. Ligand selectivity of D2 dopamine receptors is modulated by changes in local dynamics produced by sodium binding. J Pharmacol Exp Ther. 2009;328(1):40–54. https://doi.org/10.1124/jpet.108.141531.CrossRefPubMed

43.

Smith NJ, Bennett KA, Milligan G. When simple agonism is not enough: emerging modalities of GPCR ligands. Mol Cell Endocrinol. 2011;331(2):241–7. https://doi.org/10.1016/j.mce.2010.07.009.CrossRefPubMed

44.

Yang D, Zhou Q, Labroska V, Qin S, Darbalaei S, Wu Y, Yuliantie E, Xie L, Tao H, Cheng J, Liu Q, Zhao S, Shui W, Jiang Y, Wang MW. G protein-coupled receptors: structure- and function-based drug discovery. Signal Transduct Target Ther. 2021;6(1):7. https://doi.org/10.1038/s41392-020-00435-w.CrossRefPubMedPubMedCentral

45.

Lappano R, Maggiolini M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov. 2011;10(1):47–60. https://doi.org/10.1038/nrd3320.CrossRefPubMed

46.

Gaylinn BD, Harrison JK, Zysk JR, Lyons CE, Lynch KR, Thorner MO. Molecular cloning and expression of a human anterior pituitary receptor for growth hormone-releasing hormone. Mol Endocrinol. 1993;7(1):77–84. https://doi.org/10.1210/mend.7.1.7680413.CrossRefPubMed

47.

Fredriksson R, Lagerstrom MC, Lundin LG, Schiöth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol. 2003;63:1256–72. https://doi.org/10.1124/mol.63.6.1256.CrossRefPubMed

48.

Fredriksson R, Schiöth HB. The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol. 2005;67(5):1414–25. https://doi.org/10.1124/mol.104.009001.CrossRefPubMed

49.

Attwood TK, Findlay JB. Fingerprinting G-protein-coupled receptors. Protein Eng. 1994;7:195–203. https://doi.org/10.1093/protein/7.2.195.CrossRefPubMed

50.

Maeda A, Okano K, Park PS, Lem J, Crouch RK, Maeda T, Palczewski K. Palmitoylation stabilizes unliganded rodopsin. Proc Natl Acad Sci U S A. 2010;107(18):8428–33. https://doi.org/10.1073/pnas.1000640107.CrossRefPubMedPubMedCentral

51.

Tobin AB. G-protein-coupled receptor phosphorylation: where, when and by whom. Br J Pharmacol. 2008;153(Suppl 1):S167–76. https://doi.org/10.1038/sj.bjp.0707662.CrossRefPubMedPubMedCentral

52.

Katritch V, Cherezov V, Stevens RC. Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol Sci. 2012;33(1):17–27. https://doi.org/10.1016/j.tips.2011.09.003.CrossRefPubMed

53.

Rekasi Z, Czompoly T, Schally AV, Halmos G. Isolation and sequencing of cDNAs for splice variants of growth hormone releasing hormone receptors from human cancers. Proc Natl Acad Sci USA. 2000;97:10561–6. https://doi.org/10.1073/pnas.180313297.CrossRefPubMedPubMedCentral

54.

Vamvakopoulos NC, Kunz J, Olberding U, Scherer SW, Sioutopoulou TO, Schneider V, Durkin AS, Nierman WC. Mapping the human growth hormone releasing hormone receptor [GHRHR] gene to the short arm of chromosome 7 [7p13-p21] near the epidermal growth factor receptor [EGFR]. Genomics. 1994;20:338–40. https://doi.org/10.1006/geno.1994.1185.CrossRefPubMed

55.

Tang J, Lagacé G, Castagné J, Collu R. Identification of human growth hormone-releasing hormone receptor splicing variants. J Clin Endocrinol Metab. 1995;80(8):2381–7. https://doi.org/10.1210/jcem.80.8.7629234.CrossRefPubMed

56.

Halmos G, Schally AV, Czompoly T, Krupa M, Varga JL, Rekasi Z. Expression of growth hormone-releasing hormone and its receptor splice variants in human prostate cancer. J Clin Endocrinol Metab. 2002;87(10):4707–14. https://doi.org/10.1210/jc.2002-020347.CrossRefPubMed

57.

Pozsgai E, Schally AV, Hocsak E, Zarandi M, Rick F, Bellyei S. The effect of a novel antagonist of growth hormone releasing hormone on cell proliferation and on the key cell signaling pathways in nine different breast cancer cell lines. Int J Oncol. 2011;39(4):1025–32. https://doi.org/10.3892/ijo.2011.1098.CrossRefPubMed

58.

Schally AV, Varga JL, Engel JB. Antagonists of growth-hormone-releasing hormone: an emerging new therapy for cancer. Nat Clin Pract Endocrinol Metab. 2008;4(1):33–43. https://doi.org/10.1038/ncpendmet0677.CrossRefPubMed

59.

Schally AV, Wang H, He J, Cai R, Sha W, Popovics P, Perez R, Vidaurre I, Zhang X. Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH. Proc Natl Acad Sci U S A. 2018;115(47):12028–33. https://doi.org/10.1073/pnas.1813375115.CrossRefPubMedPubMedCentral

60.

Szabo Z, Juhasz E, Schally AV, Dezso B, Huga S, Hernadi Z, Halmos G, Kiss C. Expression of growth hormone-releasing hormone and its receptor splice variants in primary human endometrial carcinomas: novel therapeutic approaches. Molecules. 2022;27(9): 2671. https://doi.org/10.3390/molecules27092671.CrossRefPubMedPubMedCentral

61.

Chopin LK, Herington AC. A potential autocrine pathway for growth hormone releasing hormone (GHRH) and its receptor in human prostate cancer cell lines. Prostate. 2001;49(2):116–21. https://doi.org/10.1002/pros.1125.CrossRefPubMed

62.

Fahrenholtz CD, Rick FG, Garcia MI, Zarandi M, Cai RZ, Block NL, Schally AV, Burnstein KL. Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer. Proc Natl Acad Sci USA. 2014;111(3):1084–9. https://doi.org/10.1073/pnas.1323102111.CrossRefPubMedPubMedCentral

63.

Plonowski A, Schally AV, Busto R, Krupa M, Varga JL, Halmos G. Expression of growth hormone-releasing hormone (GHRH) and splice variants of GHRH receptors in human experimental prostate cancers. Peptides. 2002;23(6):1127–33. https://doi.org/10.1016/S0196-9781(02)00043-8.CrossRefPubMed

64.

Chatzistamou I, Volakaki AA, Schally AV, Kiaris H, Kittas C. Expression of growth hormone–releasing hormone receptor splice variant 1 in primary human melanomas. Regul Pept. 2008;147:33–6. https://doi.org/10.1016/j.regpep.2007.12.008.CrossRefPubMed

65.

Duc NM, Kim HR, Chung KY. Structural mechanism of G protein activation by G protein- coupled receptor. Eur J Pharmacol. 2015;763(Pt B):214–22. https://doi.org/10.1016/j.ejphar.2015.05.016.CrossRefPubMed

66.

Abboud D, Daly AF, Dupuis N, Bahri MA, Inoue A, Chevigné A, Ectors F, Plenevaux A, Pirotte B, Beckers A, Hanson J. GPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11. Nat Commun. 2020;11(1):4752. https://doi.org/10.1038/s41467-020-18500-x.CrossRefPubMedPubMedCentral

67.

Kankanamge D, Tennakoon M, Karunarathne A, Gautam N. G protein gamma subunit, a hidden master regulator of GPCR signaling. J Biol Chem. 2022;298(12): 102618. https://doi.org/10.1016/j.jbc.2022.102618.CrossRefPubMedPubMedCentral

68.

Bindzi J, Yang Y, Yan X, Zhong Y, Tian Y. Growth Hormone Releasing Hormone Receptors Antagonists and Cancers: Do GHRH-R Antagonists Play a Role in the Management of Prostate Cancer? Open J Urology. 2020;10:201–10. https://doi.org/10.4236/oju.2020.106023.CrossRef

69.

Zhang H, Liu Y, Liu J, Chen J, Wang J, Hua H, Jiang Y. cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment. J Hematol Oncol. 2024;17(1):5. https://doi.org/10.1186/s13045-024-01524-x.CrossRefPubMedPubMedCentral

70.

Bonert VS, Melmed S. Growth Hormone. In: Melmed S, editor. The Pituitary (Fourth Edition), Academic Press; 2017. pp 85–127. https://doi.org/10.1016/B978-0-12-804169-7.00004-0.

71.

Bonnefont X, Lacampagne A, Sanchez-Hormigo A, Fino E, Creff A, Mathieu MN, Smallwood S, Carmignac D, Fontanaud P, Travo P, Alonso G, Courtois-Coutry N, Pincus SM, Robinson IC, Mollard P. Revealing the large-scale network organization of growth hormone-secreting cells. Proc Natl Acad Sci USA. 2005;102(46):16880–5. https://doi.org/10.1073/pnas.0508202102.CrossRefPubMedPubMedCentral

72.

Vélez EJ, Unniappan S. Nesfatin-1 and nesfatin-1-like peptide suppress growth hormone synthesis via the AC/PKA/CREB pathway in mammalian somatotrophs. Sci Rep. 2020;10(1):16686. https://doi.org/10.1038/s41598-020-73840-4.CrossRefPubMedPubMedCentral

73.

Cohen LE. Genetic regulation of the embryology of the pituitary gland and somatotrophs. Endocrine. 2000;12(2):99–106. https://doi.org/10.1385/ENDO:12:2:99.CrossRefPubMed

74.

Norman C, Rollene NL, Erickson D, Miles JM, Bowers CY, Veldhuis JD. Estradiol regulates GH-releasing peptide’s interactions with GH-releasing hormone and somatostatin in postmenopausal women. Eur J Endocrinol. 2014;170(1):121–9. https://doi.org/10.1530/EJE-13-0733.CrossRefPubMed

75.

Kiaris H, Chatzistamou I, Papavassiliou AG, Schally AV. Growth hormone-releasing hormone: not only a neurohormone. Trends Endocrinol Metab. 2011;22:311–7. https://doi.org/10.1016/j.tem.2011.03.006.CrossRefPubMed

76.

Rick FG, Schally AV, Szalontay L, Block NL, Szepeshazi K, Nadji M, Zarandi M, Hohla F, Buchholz S, Seitz S. Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases. Proc Natl Acad Sci USA. 2012;109(5):1655–60. https://doi.org/10.1073/pnas.1120588109.CrossRefPubMedPubMedCentral

77.

Pombo CM, Zalvide J, Gaylinn BD, Diéguez C. Growth hormone-releasing hormone stimulates mitogen-activated protein kinase. Endocrinology. 2000;141:2113–9. https://doi.org/10.1210/endo.141.6.7513.CrossRefPubMed

78.

Siriwardana G, Bradford A, Coy D, Zeitler P. Autocrine/paracrine regulation of breast cancer cell proliferation by growth hormone releasing hormone via Ras, Raf, and mitogen-activated protein kinase. Mol Endocrinol. 2006;20:2010–9. https://doi.org/10.1210/me.2005-0001.CrossRefPubMed

79.

Zeitler P, Siriwardana G. Stimulation of mitogen-activated protein kinase pathway in rat somatotrophs by growth hormone-releasing hormone. Endocrine. 2000;12:257–64. https://doi.org/10.1385/ENDO:12:3:257.CrossRefPubMed

80.

Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin Cancer Biol. 2019;59:125–32. https://doi.org/10.1016/j.semcancer.2019.07.009.CrossRefPubMed

81.

Gao N, Zhang Z, Jiang BH, Shi X. Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer. Biochem Biophys Res Commun. 2003;310(4):1124–32. https://doi.org/10.1016/j.bbrc.2003.09.132.CrossRefPubMed

82.

Mengie Ayele T, Tilahun Muche Z, Behaile Teklemariam A, Bogale Kassie A, Chekol AE. Role of JAK2/STAT3 signaling pathway in the tumorigenesis, chemotherapy resistance, and treatment of solid tumors: a systemic review. J Inflamm Res. 2022;15:1349–64. https://doi.org/10.2147/JIR.S353489.CrossRefPubMedPubMedCentral

83.

Siejka A, Schally AV, Block NL, Barabutis N. Antagonists of growth hormone-releasing hormone inhibit the proliferation of human benign prostatic hyperplasia cells. Prostate. 2010;70(10):1087–93. https://doi.org/10.1002/pros.21142.CrossRefPubMed

84.

Abdulghani J, Gu L, Dagvadorj A, Lutz J, Leiby B, Bonuccelli G, Lisanti MP, Zellweger T, Alanen K, Mirtti T, Visakorpi T, Bubendorf L, Nevalainen MT. Stat3 promotes metastatic progression of prostate cancer. Am J Pathol. 2008;172(6):1717–28. https://doi.org/10.2353/ajpath.2008.071054.CrossRefPubMedPubMedCentral

85.

Senarath K, Kankanamge D, Samaradivakara S, Ratnayake K, Tennakoon M, Karunarathne A. Regulation of G Protein βγ Signaling. Int Rev Cell Mol Biol. 2018;339:133–91. https://doi.org/10.1016/bs.ircmb.2018.02.008.CrossRefPubMed

86.

Delcourt N, Bockaert J, Marin P. GPCR-jacking: from a new route in RTK signalling to a new concept in GPCR activation. Trends Pharmacol Sci. 2007;28(12):602–7. https://doi.org/10.1016/j.tips.2007.09.007.CrossRefPubMed

87.

Pyne NJ, Pyne S. Receptor tyrosine kinase-G-protein-coupled receptor signalling platforms: out of the shadow? Trends Pharmacol Sci. 2011;32(8):443–50. https://doi.org/10.1016/j.tips.2011.04.002.CrossRefPubMed

88.

George AJ, Hannan RD, Thomas WG. Unravelling the molecular complexity of GPCR-mediated EGFR transactivation using functional genomics approaches. FEBS J. 2013;280(21):5258–68. https://doi.org/10.1111/febs.12509.CrossRefPubMed

89.

Sur S, Agrawal DK. Transactivation of EGFR by G protein-coupled receptor in the pathophysiology of intimal hyperplasia. Curr Vasc Pharmacol. 2014;12(2):190–201. https://doi.org/10.2174/1570161112666140226123745.CrossRefPubMed

90.

Kilpatrick LE, Hill SJ. Transactivation of G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs): Recent insights using luminescence and fluorescence technologies. Curr Opin Endocr Metab Res. 2021;16:102–12. https://doi.org/10.1016/j.coemr.2020.10.003.CrossRefPubMedPubMedCentral

91.

Muñoz-Moreno L, Arenas MI, Carmena MJ, Schally AV, Prieto JC. Bajo AM Growth Hormone-Releasing Hormone Antagonists Abolish the Transactivation of Human Epidermal Growth Factor Receptors in Advanced Prostate Cancer Models. Invest New Drugs. 2014;32:871–82. https://doi.org/10.1007/s10637-014-0131-4.CrossRefPubMed

92.

Muñoz-Moreno L, Bajo AM, Prieto JC, Carmena MJ. Growth hormone-releasing hormone (GHRH) promotes metastatic phenotypes through EGFR/HER2 transactivation in prostate cancer cells. Mol Cell Endocrinol. 2017;446:59–69. https://doi.org/10.1016/j.mce.2017.02.011.CrossRefPubMed

93.

Di Lorenzo G, Tortora G, D’Armiento FP, De Rosa G, Staibano S, Autorino R, D’Armiento M, De Laurentiis M, De Placido S, Catalano G, Bianco AR, Ciardiello F. Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clin Cancer Res. 2002;8(11):3438–44.PubMed

94.

Berger R, Lin DI, Nieto M, Sicinska E, Garraway LA, Adams H, Signoretti S, Hahn WC, Loda M. Androgen-dependent regulation of Her-2/neu in prostate cancer cells. Cancer Res. 2006;66(11):5723–8. https://doi.org/10.1158/0008-5472.CAN-05-3928.CrossRefPubMed

95.

Kiaris H, Chatzistamou I, Schally AV, Halmos G, Varga JL, Koutselini H, Kalofoutis A. Ligand- dependent and -independent effects of splice variant 1 of growth hormone-releasing hormone receptor. Proc Natl Acad Sci USA. 2003;100:9512–7. https://doi.org/10.1073/pnas.1533185100.CrossRefPubMedPubMedCentral

96.

Cong Z, Zhou F, Zhang C, Zou X, Zhang H, Wang Y, Zhou Q, Cai X, Liu Q, Li J, Shao L, Mao C, Wang X, Wu J, Xia T, Zhao LH, Jiang H, Zhang Y, Xu HE, Cheng X, Yang D, Wang MW. Constitutive signal bias mediated by the human GHRHR splice variant 1. Proc Natl Acad Sci USA. 2021;118(40): e2106606118. https://doi.org/10.1073/pnas.2106606118.CrossRefPubMedPubMedCentral

97.

Singh O, Bolla SR. Anatomy, Abdomen and Pelvis, Prostate. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.

98.

Pletcher A, Shibata M. Prostate organogenesis. Development. 2022;149(12):dev200394. https://doi.org/10.1242/dev.200394.CrossRefPubMedPubMedCentral

99.

Halmos G, Szabo Z, Juhasz E, Schally AV. Signaling mechanism of growth hormone-releasing hormone receptor. Vitam Horm. 2023;123:1–26. https://doi.org/10.1016/bs.vh.2023.06.004.CrossRefPubMed

100.

Rick FG, Schally AV, Block NL, Nadji M, Szepeshazi K, Zarandi M, Vidaurre I, Perez R, Halmos G, Szalontay L. Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia. Proc Natl Acad Sci U S A. 2011;108(9):3755–60. https://doi.org/10.1073/pnas.1018086108.

101.

Popovics P, Cai R, Sha W, Rick FG, Schally AV. Growth hormone-releasing hormone antagonists reduce prostatic enlargement and inflammation in carrageenan-induced chronic prostatitis. Prostate. 2018;78(13):970–80. https://doi.org/10.1002/pros.23655.CrossRefPubMed

102.

Barabutis N, Akhter MS, Kubra KT, Jackson K. Growth hormone-releasing hormone in endothelial inflammation. Endocrinology. 2022;164(2): 209. https://doi.org/10.1210/endocr/bqac209.CrossRef

103.

Mughees M, Kaushal JB, Sharma G, Wajid S, Batra SK, Siddiqui JA. Chemokines and cytokines: axis and allies in prostate cancer pathogenesis. Semin Cancer Biol. 2022;86(Pt 3):497–512. https://doi.org/10.1016/j.semcancer.2022.02.017.CrossRefPubMedPubMedCentral

104.

Muñoz-Moreno L, Schally AV, Prieto JC, Carmena MJ, Bajo AM. Growth hormone-releasing hormone receptor antagonists modify molecular machinery in the progression of prostate cancer. Prostate. 2018;78(12):915–26. https://doi.org/10.1002/pros.23648.CrossRefPubMed

105.

Muñoz-Moreno L, Carmena MJ, Prieto JC, Schally AV, Bajo AM. Tumorigenic transformation of human prostatic epithelial cell line RWPE-1 by growth hormone-releasing hormone (GHRH). Prostate. 2022;82(8):933–41. https://doi.org/10.1002/pros.24339.CrossRefPubMedPubMedCentral

106.

Muñoz-Moreno L, Carmena MJ, Schally AV, Prieto JC, Bajo AM. Stimulation of neuroendocrine differentiation in prostate cancer cells by GHRH and its blockade by GHRH antagonists. Invest New Drugs. 2020;38(3):746–54. https://doi.org/10.1007/s10637-019-00831-2.CrossRefPubMed

107.

Recouvreux MV, Wu JB, Gao AC, Zonis S, Chesnokova V, Bhowmick N, Chung LW, Melmed S. Androgen receptor regulation of local growth hormone in prostate cancer cells. Endocrinology. 2017;158(7):2255-68. https://doi.org/10.1210/en.2016-19.

108.

Robberecht P, Coy DH, Waelbroeck M, Heiman ML, de Neef P, Camus JC, Christophe J. Structural requirements for the activation of rat anterior pituitary adenylate cyclase by growth hormone-releasing factor (GRF): discovery of (N-Ac-Tyr1, D-Arg2)-GRF(1–29)-NH2 as a GRF antagonist on membranes. Endocrinology. 1985;117(5):1759–64. https://doi.org/10.1210/endo-117-5-1759.CrossRefPubMed

109.

Zarandi M, Horvath JE, Halmos G, Pinski J, Nagy A, Groot K, Rekasi Z, Schally AV. Synthesis and biological activities of highly potent antagonists of growth hormone-releasing hormone. Proc Natl Acad Sci U S A. 1994;91(25):12298–302. https://doi.org/10.1073/pnas.91.25.12298.CrossRefPubMedPubMedCentral

110.

Varga JL, Schally AV, Csernus VJ, Zarándi M, Halmos G, Groot K, Rékási Z. Synthesis and biological evaluation of antagonists of growth hormone-releasing hormone with high and protracted in vivo activities. Proc Natl Acad Sci U S A. 1999;96(2):692–7. https://doi.org/10.1073/pnas.96.2.692.CrossRefPubMedPubMedCentral

111.

Buchholz S, Schally AV, Engel JB, Hohla F, Heinrich E, Koester F, Varga JL, Halmos G. Potentiation of mammary cancer inhibition by combination of antagonists of growth hormone-releasing hormone with docetaxel. Proc Natl Acad Sci USA. 2007;104(6):1943–6. https://doi.org/10.1073/pnas.0610860104.CrossRefPubMedPubMedCentral

112.

Cai R, Zhang X, Wang H, Cui T, Halmos G, Sha W, He J, Popovics P, Vidaurre I, Zhang C, Mirsaeidi M, Schally AV. Synthesis of potent antagonists of receptors for growth hormone-releasing hormone with antitumor and anti-inflammatory activity. Peptides. 2022;150: 170716. https://doi.org/10.1016/j.peptides.2021.170716.CrossRefPubMed

113.

Schally AV. New approaches to the therapy of various tumors based on peptide analogues. Horm Metab Res. 2008;40(5):315–22. https://doi.org/10.1055/s-2008-1073142.CrossRefPubMed

114.

Zarandi M, Cai R, Kovacs M, Popovics P, Szalontay L, Cui T, Sha W, Jaszberenyi M, Varga J, Zhang X, Block NL, Rick FG, Halmos G, Schally AV. Synthesis and structure-activity studies on novel analogs of human growth hormone releasing hormone (GHRH) with enhanced inhibitory activities on tumor growth. Peptides. 2017;89:60–70. https://doi.org/10.1016/j.peptides.2017.01.009.CrossRefPubMed

115.

Pinski J, Schally AV, Groot K, Halmos G, Szepeshazi K, Zarandi M, Armatis P. Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone. J Natl Cancer Inst. 1995;87(23):1787–94. https://doi.org/10.1093/jnci/87.23.1787.CrossRefPubMed

116.

Pinski J, Schally A, Jungwirth A, Groot K, Halmos G, Armatis P, Zarandi M, Vadillobuenfil M. Inhibition of growth of human small cell and non-small cell lung carcinomas by antagonists of growth hormone-releasing hormone (GH-RH). Int J Oncol. 1996;9(6):1099–105. https://doi.org/10.3892/ijo.9.6.1099.CrossRefPubMed

117.

Schally AV, Varga JL. Antagonists of growth hormone-releasing hormone in oncology. Comb Chem High Throughput Screen. 2006;9(3):163–70. https://doi.org/10.2174/138620706776055449.CrossRefPubMed

118.

Engel JB, Keller G, Schally AV, Toller GL, Groot K, Havt A, Armatis P, Zarandi M, Varga JL, Halmos G. Inhibition of growth of experimental human endometrial cancer by an antagonist of growth hormone-releasing hormone. J Clin Endocrinol Metab. 2005;90(6):3614–21. https://doi.org/10.1210/jc.2004-2179.CrossRefPubMed

119.

Szepeshazi K, Schally AV, Groot K, Armatis P, Halmos G, Herbert F, Szende B, Varga JL, Zarandi M. Antagonists of growth hormone-releasing hormone (GH-RH) inhibit IGF-II production and growth of HT-29 human colon cancers. Br J Cancer. 2000;82(10):1724–31. https://doi.org/10.1054/bjoc.2000.1223.CrossRefPubMedPubMedCentral

120.

Kiaris H, Schally AV, Varga JL, Groot K, Armatis P. Growth hormone-releasing hormone: an autocrine growth factor for small cell lung carcinoma. Proc Natl Acad Sci USA. 1999;96(26):14894–8. https://doi.org/10.1073/pnas.96.26.14894.CrossRefPubMedPubMedCentral

121.

Braczkowski R, Schally AV, Plonowski A, Varga JL, Groot K, Krupa M, Armatis P. Inhibition of proliferation in human MNNG/HOS osteosarcoma and SK-ES-1 Ewing sarcoma cell lines in vitro and in vivo by antagonists of growth hormone-releasing hormone: effects on insulin-like growth factor II. Cancer. 2002;95(8):1735–45. https://doi.org/10.1002/cncr.10865.CrossRefPubMed

122.

Kiaris H, Schally AV. Decrease in telomerase activity in U-87MG human glioblastomas after treatment with an antagonist of growth hormone-releasing hormone. Proc Natl Acad Sci USA. 1999;96(1):226–31. https://doi.org/10.1073/pnas.96.1.226.CrossRefPubMedPubMedCentral

123.

Keller G, Schally AV, Groot K, Toller GL, Havt A, Köster F, Armatis P, Halmos G, Zarandi M, Varga JL, Engel JB. Effective treatment of experimental human non-Hodgkin’s lymphomas with antagonists of growth hormone-releasing hormone. Proc Natl Acad Sci U S A. 2005;102(30):10628–33. https://doi.org/10.1073/pnas.0504102102.CrossRefPubMedPubMedCentral

124.

Hohla F, Buchholz S, Schally AV, Seitz S, Rick FG, Szalontay L, Varga JL, Zarandi M, Halmos G, Vidaurre I, Krishan A, Kurtoglu M, Chandna S, Aigner E, Datz C. GHRH antagonist causes DNA damage leading to p21 mediated cell cycle arrest and apoptosis in human colon cancer cells. Cell Cycle. 2009;8(19):3149–56. https://doi.org/10.4161/cc.8.19.9698.CrossRefPubMed

125.

Stangelberger A, Schally AV, Varga JL, Hammann BD, Groot K, Halmos G, Cai RZ, Zarandi M. Antagonists of growth hormone releasing hormone (GHRH) and of bombesin/gastrin releasing peptide (BN/GRP) suppress the expression of VEGF, bFGF, and receptors of the EGF/HER family in PC-3 and DU-145 human androgen-independent prostate cancers. Prostate. 2005;64(3):303–15. https://doi.org/10.1002/pros.20262.CrossRefPubMed

126.

Bellyei S, Schally AV, Zarandi M, Varga JL, Vidaurre I, Pozsgai E. GHRH antagonists reduce the invasive and metastatic potential of human cancer cell lines in vitro. Cancer Lett. 2010;293(1):31–40. https://doi.org/10.1016/j.canlet.2009.12.014.CrossRefPubMed

127.

Kanashiro CA, Schally AV, Zarandi M, Hammann BD, Varga JL. Suppression of growth of H-69 small cell lung carcinoma by antagonists of growth hormone releasing hormone and bombesin is associated with an inhibition of protein kinase C signaling. Int J Cancer. 2004;112(4):570–6. https://doi.org/10.1002/ijc.20437.CrossRefPubMed

128.

Guo J, Schally AV, Zarandi M, Varga J, Leung PC. Antiproliferative effect of growth hormone-releasing hormone (GHRH) antagonist on ovarian cancer cells through the EGFR-Akt pathway. Reprod Biol Endocrinol. 2010;8:54. https://doi.org/10.1186/1477-7827-8-54.CrossRefPubMedPubMedCentral

129.

Popovics P, Schally AV, Salgueiro L, Kovacs K, Rick FG. Antagonists of growth hormone-releasing hormone inhibit proliferation induced by inflammation in prostatic epithelial cells. Proc Natl Acad Sci USA. 2017;114(6):1359–64. https://doi.org/10.1073/pnas.1620884114.CrossRefPubMedPubMedCentral

130.

Rick FG, Saadat SH, Szalontay L, Block NL, Kazzazi A, Djavan B, Schally AV. Hormonal manipulation of benign prostatic hyperplasia. Curr Opin Urol. 2013;23(1):17–24. https://doi.org/10.1097/MOU.0b013e32835abd18.CrossRefPubMed

131.

Rick FG, Schally AV, Block NL, Abi-Chaker A, Krishan A, Szalontay L. Mechanisms of synergism between antagonists of growth hormone-releasing hormone and antagonists of luteinizing hormone-releasing hormone in shrinking experimental benign prostatic hyperplasia. Prostate. 2013;73(8):873–83. https://doi.org/10.1002/pros.22633.CrossRefPubMed

132.

Barabutis N, Schally AV. Antioxidant activity of growth hormone-releasing hormone antagonists in LNCaP human prostate cancer line. Proc Natl Acad Sci U S A. 2008;105(51):20470–5. https://doi.org/10.1073/pnas.0811209106.CrossRefPubMedPubMedCentral

133.

Ayhan-Sahin B, Apaydın ZE, Obakan-Yerlikaya P, Arisan ED, Coker-Gurkan A. Synthesis and characterization of novel ssDNA X-aptamers targeting Growth Hormone Releasing Hormone (GHRH). PLoS ONE. 2022;17(1): e0260144. https://doi.org/10.1371/journal.pone.0260144.CrossRefPubMedPubMedCentral

134.

Matsoukas MT, Radomsky T, Panagiotopoulos V, Preez RD, Papadourakis M, Tsianakas K, Millar RP, Anderson RC, Spyroulias GA, Newton CL. Identification of small-molecule antagonists targeting the growth hormone releasing hormone receptor (GHRHR). J Chem Inf Model. 2024. https://doi.org/10.1021/acs.jcim.4c00577.CrossRefPubMedPubMedCentral

Title: GHRH and the prostate
Authors: Laura Muñoz-Moreno
Irene D. Román
Ana M. Bajo
Publication date: 07-11-2024
Publisher: Springer US
Keywords: Prostate Cancer
Prostate Cancer
Published in: Reviews in Endocrine and Metabolic Disorders
Print ISSN: 1389-9155
Electronic ISSN: 1573-2606
DOI: https://doi.org/10.1007/s11154-024-09922-9

Keynote series | Spotlight on menopause

Menopause
Video Series

Menopause can have a significant impact on the body, with effects ranging beyond the endocrine and reproductive systems. Learn about the broader systemic effects of menopause, so you can help patients in your clinics through the transition.

Launching: Thursday 12th December 2024

Prof. Martha Hickey

Dr. Claudia Barth

Dr. Samar El Khoudary

Developed by: Springer Medicine

Keynote webinar | Spotlight on adolescent vaping

Live
Webinar | 29-01-2025 | 18:00 (CET)

Growing numbers of young people are using e-cigarettes, despite warnings of respiratory effects and addiction. How can doctors tackle the epidemic, and what health effects should you prepare to manage in your clinics?

Watch it live: Wednesday 29th January, 18:00-19:30 CET

Prof. Ann McNeill

Dr. Debbie Robson

Benji Horwell

Developed by: Springer Medicine

Join the webinar

Keynote webinar | Spotlight on modern management of frailty

Frailty in Geriatric Patients
On-demand webinar

Frailty has a significant impact on health and wellbeing, especially in older adults. Our experts explain the factors that contribute to the development of frailty and how you can manage the condition and reduce the risk of disability, dependency, and mortality in your patients.

Prof. Alfonso Cruz-Jentoft

Prof. Barbara C. van Munster

Prof. Mirko Petrovic

Developed by: Springer Medicine

Watch now

A quick guide to ECGs

Electrocardiography
Training Course

Improve your ECG interpretation skills with this comprehensive, rapid, interactive course. Expert advice provides detailed feedback as you work through 50 ECGs covering the most common cardiac presentations to ensure your practice stays up to date.

PD Dr. Carsten W. Israel

Developed by: Springer Medizin

Start the cases

At a glance: The STEP trials

Obesity
Clinical Trial Summary

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote series | Spotlight on menopause

Springer Medicine

Abstract

Please log in to get access to this content

Keynote series | Spotlight on menopause

Keynote webinar | Spotlight on adolescent vaping

Keynote webinar | Spotlight on modern management of frailty

A quick guide to ECGs

At a glance: The STEP trials