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Luteinizing Hormone-Releasing Hormone Induces Nuclear Factor B-Activation and Inhibits Apoptosis in Ovarian Cancer Cells

Department of Gynecology and Obstetrics, Georg-August University, D-37070 Göttingen, Germany

Address correspondence and requests for reprints to: Günter Emons, M.D., Georg-August University, Department of Gynecology and Obstetrics, Robert-Koch Street 40, D-37075 Göttingen, Germany. E-mail: emons{at}med.uni-goettingen.de

More than 80% of human ovarian cancers express LHRH and its receptor as part of a negative autocrine mechanism of growth control. This study was conducted to investigate whether LHRH affects apoptosis in ovarian cancer. EFO-21 and EFO-27 ovarian cancer cells were treated with LHRH agonist Triptorelin or with cytotoxic agent Doxorubicin in the absence or presence of Triptorelin. Apoptotic cells were quantified by flow cytometry. Expression of nuclear factor kappa B (NFB) was assessed by RT-PCR and immunoblotting. For determination of Triptorelin-induced NFB activation, cells were transfected with a NFB-secreted alkaline phosphatase reporter gene plasmid (pNFB-SEAP) and cultured for 96 h with or without Triptorelin. The causal relation between Triptorelin-induced NFB activation and Triptorelin-induced protection against apoptosis was investigated using SN50, an inhibitor for nuclear translocation of activated NFB. Apoptosis induction by Triptorelin was never observed. Treatment with Doxorubicin (1 nmol/L) for 72 h increased the percentage of apoptotic cells in EFO-21 and EFO-27 ovarian cancer cell lines to 31% or 34%, respectively. In cultures treated simultaneously with Triptorelin (100 nmol/L), the percentage of apoptotic cells was reduced significantly, to 17% or 18%, respectively (P < 0.001). RT-PCR and immunoblotting experiments showed that NFB subunits p50 and p65 were expressed by ovarian cancer cell lines EFO-21 and EFO-27. When EFO-21 or EFO-27 cells were transfected with pNFB-SEAP and subsequently treated with Triptorelin (100 nmol/L), NFB-induced SEAP expression increased 5.3-fold or 4.7-fold, respectively (P < 0.001). Triptorelin-induced reduction of Doxorubicin-induced apoptosis was blocked by SN50-mediated inhibition of NFB translocation into the nucleus. We conclude that LHRH induces activation of NFB and thus reduces Doxorubicin-induced apoptosis in human ovarian cancer cells. This possibility to protect ovarian cancer cells from programmed cell death is an important feature in LHRH signaling in ovarian tumors, apart from the inhibitory interference with the mitogenic pathway.

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