Investigation on the regulation of gonadotropin-releasing hormone (GnRH) and FSH secretion  Page description

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Details of project

  
Identifier
46098
Type K
Principal investigator Kovács, Magdolna
Title in Hungarian A gonadotropin-releasing hormon (GnRH) és az FSH szekréció szabályozásának vizsgálata
Title in English Investigation on the regulation of gonadotropin-releasing hormone (GnRH) and FSH secretion
Panel Cellular and Developmental Biology
Department or equivalent Institute of Anatomy (University of Pécs)
Participants Csernus, Valér
Horváth, Judit
Rékási, Zoltán
Starting date 2004-01-01
Closing date 2009-06-30
Funding (in million HUF) 4.472
FTE (full time equivalent) 0.00
state closed project





 

Final report

  
Results in Hungarian
A lamprey gonadotropin-releasing hormon (GnRH)-III különböző analógjait hoztuk létre, és vizsgáltuk azok FSH/LH- felszabadító, valamint tumorgátló hatásukat humán emlő carcinoma sejteken. Az Arg8-GnRH-III specifikusan kötődik az emlős GnRH receptorhz, és 3-11-szer nagyobb gonadotropin-releasing hatáserősséget mutat mint a GnRH-III, az emlős GnRH-hoz viszonyított erőssége azonban 1% alatt van. A tumorgátló aktivitás fokozása céljából létrehozott dimer analógok antitumor aktivitása és enzimekkel szembeni stabilitása fokozódott, míg endokrín hatáserőssége lényegesen csökkent. A GnRH-III copolymer konjugátumának endokrín aktivitása közel zéró, ugyanakkor tumorgátló hatáserőssége humán emlőcarcinoma sejteken 2-3-szoros. Adataink arra utalnak, hogy a GnRH analógok tumorgátló szelektivitása fokozható. A klinikumban is használatos GnRH antagonista Cetrorelix alakalmazásával igazoltuk, hogy az analóg alkalmas a hypophysis-gonád tengely részleges gátlására, és ezáltal az endometriosis és a prostata hyperplasia kezelésére is. Kimutattuk, hogy a GnRH-gonadotropin rendszer részt vesz a hypophyseális inhibin/aktivin és follisztatin génexpresszió szabályozásában. Fő szabályozó a GnRH, amely stimulálja a follisztatin génexpressziót, az inhibin-specifikus α lánc és a βB alegység génexpressziót pedig gátolja. A βA lánc mRNS expresszója jelentősen kisebb, mint a βB láncé, ími arra utal, hogy a hypophysisben főként az inhibin/aktivin B forma fordul elő.
Results in English
We developed various analogs of lamprey gonadotropin-releasing hormon (GnRH)-III and investigated their LH/FSH-releasing potency and antiproliferative activity on human breast cancer cells. Arg8-GnRH-III specifically binds to the mammalian (m) GnRH receptor and has 3-11 fold gonadotropin-releasing potency compared to GnRH-III but less than 1% potency compared to mGnRH. Dimer analogs, which were developed to improve the anticancer potency, showed higher stability against degrading enzymes, stronger anticancer effects, and weaker endocrine potency. A copolymer conjugate of GnRH-III had 2-3 fold anticancer activity while loosing endocrine potency. Our data show that the anticancer selectivity of the GnRH analogs can be improved. Investigating the GnRH antagonist Cetrorelix, which is used in the clinical practice, we confirmed that Cetrorelix at low doses only a partially inhibit the pituitary-gonad axis and might be indicated for treatment of endometriosis and benign prostatic hyperplasia. We demonstrated that the GnRH-gonadotropin system plays a role in the regulation of gene expression of the pituitary inhibin/activin and follistatin. GnRH is the main regulator, which stimulates follistatin gene expression but inhibits the inhibin-specific α subunit and the βB gene expression. The expression of the βA subunit is significantly lower than that of the βB, indicating that the B forms of inhibin/activin are more significant in the pituitary than the A forms.
Full text https://www.otka-palyazat.hu/download.php?type=zarobeszamolo&projektid=46098
Decision
Yes





 

List of publications

  
Kovács M; Vincze B; Horváth J; Seprődi J: FSH- and LH- releasing effect compared with antitumor avtivities of gonadotropin-releasing hormone (GnRH)-III analogs., Endo 2004 The Endocrine Society's 86th Annual Meeting, New Orleans; P3-373, p530;, 2004
Kovács M; Vincze B; Horváth J; Seprődi J: Structure-activity study on the LH- and FSH-releasing and anticancer effects of gonadotropin-releasing hormone (GnRH)-III analogs., Peptides, 28:821-829, 2007
Mező G, Czajlik A, Jakab A, Farkas V, Vass E, Majer Z, Kapuvári B, Vincze B, Csuka O, Kovács M, Perczel A,, Hudecz F.: Structure-biological activity relationship of GnRH-III and its dimer derivatives., The FEBS Journal 272 : Suppl. 1,, 2005
Szabó I, Kapuvári B, Boldizsár M, Vincze B, Bősze Sz, Szabó R, Kovács M, Hudecz F, Mező G: Antiproliferative effect of GnRH-III anad GnRH-II peptide derivatives on MCF-7 and HT-29 cells., 9th Solid Phase Peptide Symposium, Norwich, UK; P-20, p19, 2007
Mező G, Czajlik A, Manea M, Jakab A, Farkas V, Majer Z, Vass E, Bodor A, Kapuvári B, Boldizsár M, Vincze B, Csuka O, Kovács M, Przybylsli M,Perczel A, Hudecz F.: Structure, enzymatic stability and antitumor activity of sea lamprey GnRH-III and its dimer derivatives., Peptides, 28:806-820, 2007
Mező G, Manea M, Szabó I, Vincze B, Kovács M: New derivatives of GnRH as potential anti-cancer therapeutic agents, Current Medicinal Chemistry 15:2366-2379, 2008
Horvath JE , Toller GL, Schally AV, Bajo A-M, Groot K: Effect of long-term treatment with low doses of the LHRH antagonist Cetrorelix on pituitary receptors for LHRH and gonadal axis in male and female rats, Proc Natl Acad Sci USA , 101:4996-5001, 2004
Kovács M., Szepesházi K., Schally AV.: Endocrine and antineoplastic effects of antagonistic and cytotoxic analogs of luteinising hormone-releasing hormone, Neuropeptides and Peptide Analogs, ISBN:978-81-308-0317-3, pp.33-57, 2009
Varga JL., Schally AV., Horvath JE., Kovacs M., Halmos G., Groot K.,Toller GL., Rekasi Z., Zarandi M.: Increased activity of antagonists of growth hormone-releasing hormone substituted at positions 8, 9 and 10, Proc Natl Acad Sci USA, 101:1708-1713, 2004
Zarándi M, Varga JL, Schally AV, Horváth JE, Toller GL, Letsch M, Groot K, Armatis P, Halmos G.: Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities., Proc Natl Acad Sci USA, 2006
Toller GL., Horvath JE., Schally AV., Halmos G., Varga JL., Groot K., Chism D., Zarandi M.: Development of polyclonal antiserum for the detection of the isoforms the receptors for human growth hormone-releasing hormone on tumors., Proc Natl Acad Sci USA, 101:15160-15165., 2004
Kovács M, Schally AV, Varga JL, Zarándi M: Endocrine and antineoplastic actions of growth hormone-releasing hormone antagonists, Current Medicinal Chemistry, 15:314-321, 2008
Kovács M., Popovics P., Rékási Z.: Regulation of pituitary inhibin mRNA expression by gonadotrpin-releasing hormone (GnRH), Endo 2008, The Endocrine Society's 90th Annual Meeting, San Francisco, P-2-672, 2008
Popovics P., Rékási Z., Kovács M.: Regulation of pituitary inhibin/activin subunits and follistatin gene expression., J. Endocrinology (submitted), 2009



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