Regulation of UT-OC-3 ovarian carcinoma cells by cytokines: inhibitory effects on cell proliferation and activation of transcription factors AP-1 and NF-kappaB

Abstract

The present study was designed to investigate the growth regulatory effects of cytokines in UT-OC-3 ovarian cystadenocarcinoma cells in vitro. The effects of interleukin-6 (IL-6), interferons a (IFN-a) and g (IFN-g), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor a (TNF-a), and transforming growth factor b1 (TGF-b1) were investigated by 125 I-deoxyuridine ( 125 IUdR) incorporation assay. In order to understand better the molecular mechanisms of the observed effects, the activation of DNA-binding proteins was studied by electrophoretic mobility shift assay. In addition, cellular DNA was tested by fragmentation analysis to determine if the most growth inhibitory cytokines are able to induce programmed cell death (apoptosis). After 48 h in culture, TGF-b1, TNF-a, IFN-a and IL-6 showed a clear inhibitory effect on 125 IUdR incorporation (P<0.005), and IFN-g and GM-CSF caused even more significant inhibition (P < 0.001). IFN-a and IFN-g were both growth inhibitory after 72 h in culture (P < 0.005). Similarly, GM-CSF induced a slight inhibition (P < 0.05), whereas TGF-b1 and TNF-a almost blocked DNA synthesis (P < 0.001) after 72 h. IL-6 had no statistically significant effect on cell proliferation after 72 h. Transcription factors AP-1 and NF-kB were both constitutively expressed in UT-OC-3 cells. The binding activity of AP-1 was found to be stimulated by the growth inhibitory cytokines, TGF-b1 and TNF-a, and the binding of NF-kB was stimulated by TNF-a. Apoptosis does not seem to be induced by any of these cytokines in the UT-OC-3 ovarian cancer cell model.

A novel approach in the treatment of neuroendocrine gastrointestinal tumors: Additive antiproliferative effects of interferon-γ and meta-iodobenzylguanidine

“…Here, we report on the antineoplastic effects of IFNγ, a cytokine which has already been shown to exert growth inhibitory effects in vitro in several non-neuroendocrine cancer models, including breast [27], hepatocellular [28], ovarian [29] and colorectal carcinoma [30,31] or glioblastoma [32]. Also in vivo , IFNγ has been demonstrated to be beneficial as a first line therapeutic agent for ovarian cancer [33] or as a supportive drug for enhanced chemoimmunotherapeutic regimes of metastatic melanoma [34].…”

Biology of the gonadotropin-releasing hormone system in gynecological cancers

“…In a study in rats, c-jun mRNA depression and endometrial epithelial cell proliferation were suggested to be linked (104). In UT-OC-3 ovarian cancer cells, cytokines have inhibitory effects on cell proliferation and activate AP-1 and NFkB (105). As the antiproliferative GnRH agonist triptorelin activates the JNK/c-jun pathway and JNK/c-jun was found to be involved in downregulation of cell proliferation in different systems, it seems reasonable to speculate that the JNK/c-jun pathway is involved in the antiproliferative actions of the GnRH agonist triptorelin.…”

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

“…In a study on rats, c-jun mRNA depression and endometrial epithelial cell proliferation were suggested to be linked (49). In UT-OC-3 ovarian cancer cells cytokines have inhibitory effects on cell proliferation and activate AP-1 and NFkB (50). Because triptorelin activates the JNK/c-jun pathway and JNK/c-jun was found to be involved in down-regulation of cell proliferation in different systems, it seems reasonable to speculate that the JNK/c-jun pathway is involved in the antiproliferative actions of this agonist.…”