Luteinizing hormone-releasing hormone induces JunD-DNA binding and extends cell cycle in human ovarian cancer cells.
Expression of luteinizing hormone-releasing hormone (LHRH) and its receptor as part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the ovary. This study was conducted to investigate whether LHRH induces activation of JunD and affects cell cycle regulation and DNA synthesis. Treatment of primary human ovarian cancer cells and human ovarian cancer cell lines EFO-21 and EFO-27 with LHRH agonist triptorelin (100 nM) resulted in an increase in G(0/1) phase and a decrease in G(2/S) phase of cell cycle. Treatment of quiescent EFO-21 or EFO-27 cells with triptorelin (100 nM) resulted in a 46.7 or 44.2-fold increase of AP-1 activation, respectively (p<0.001). Maximal binding of JunD on DNA consensus sequence was found after 4 h of treatment of quiescent EFO-21 or EFO-27 cells with triptorelin (100 nM). DNA synthesis was significantly decreased to 45.5+/-11.4% (day 0=control=100%; p<0.001) after 3 days of triptorelin (1 nM) treatment. These results suggest that LHRH agonist triptorelin induces JunD-DNA binding, resulting in reduced proliferation as indicated by increased G(0/1) phase of cell cycle and decreased DNA synthesis. Since LHRH activates nucleus factor kappa B (NF kappa B) and protects ovarian cancer cells from doxorubicin-induced apoptosis and JunD is shown to decrease cell cycle and cell proliferation, we propose that JunD activated by LHRH acts as a modulator of cell proliferation and cooperates with the anti-apoptotic and anti-mitogenic functions of LHRH.
Günthert
Andreas R
AR
Department of Gynecology and Obstetrics, Georg-August-University, Robert-Koch-Street 40, D-37075 Göttingen, Germany.
Gründker
Carsten
C
Hollmann
Kirsten
K
Emons
Günter
G
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005260:Female; D005434:Flow Cytometry; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D017329:Triptorelin Pamoate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D004273:DNA, Neoplasm; D016755:Proto-Oncogene Proteins c-jun; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D004247:DNA