Production of Steroids by Human Ovarian Surface Epithelial Cells in Culture: Possible Role of Progesterone as Growth Inhibitor

Ivarsson, Karin; Sundfeldt, Karin; Brännström, Mats; Janson, Per Olof

doi:10.1006/gyno.2001.6219

Cited by 54 publications

(37 citation statements)

References 31 publications

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“…Normal human OSE express specific receptors for FSH and LH/hCG both in vivo and in vitro (42)(43)(44). However, the findings regarding the effect of FSH and LH/hCG on OSE are inconsistent; treatment with gonadotropins stimulated OSE proliferation in some studies (43,(45)(46)(47) but was either noneffective (16) or inhibitory for other cases (48). In this study, we observed changes in N-cadherin levels at concentrations of FSH that correlate with the profile of serum concentration of FSH and LH/hCG in the normal reproductive cycle.…”

Section: Inhibitor Of Matrix Metalloproteinase Inhibits the Camp-medimentioning

confidence: 99%

“…In particular, recent data indicate that FSH, depending on its concentrations, can influence oocyte growth by regulating the ratio of Kit ligand and bone morphogenetic protein (49). The variations in hormone concentration may in fact account for the contradictory reports of FSH effects on OSE (16,43,(47)(48) and provide a possible basis for the concept that FSH can stimulate growth as well as induce apoptosis in OSE cells.…”

Section: Inhibitor Of Matrix Metalloproteinase Inhibits the Camp-medimentioning

confidence: 99%

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Gonadotropins Regulate N-cadherin-mediated Human Ovarian Surface Epithelial Cell Survival at Both Post-translational and Transcriptional Levels through a Cyclic AMP/Protein Kinase A Pathway

Pon

Auersperg

Wong

2005

Journal of Biological Chemistry

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Gonadotropins are the major regulators of ovarian function and may be involved in the etiology of ovarian cancer. In this study, we report a new mechanism whereby gonadotropins regulate the survival of human ovarian surface epithelium (OSE), the tissue of origin of epithelial ovarian carcinomas. Our results indicate that disruption of N-cadherin-mediated cell-cell adhesion is an important molecular event in the apoptosis of human OSE. Treatment with surge serum concentrations of gonadotropins reduced the amount of N-cadherin with a concomitant induction of apoptosis, and this effect was mediated by a cAMP/protein kinase A pathway but not the ERK1/2 and protein kinase C cascades. We further demonstrated that activation of the gonadotropins/ cAMP signaling pathway in human OSE led to a rapid down-regulation of N-cadherin protein level followed by a reduction at the level of N-cadherin mRNA, indicating that expression of N-cadherin was regulated by posttranslational and transcriptional mechanisms. The former mechanism was mediated by increased turnover of N-cadherin protein and could be reversed by inhibition of proteasomal or matrix metalloproteinase (MMP-2) activity. On the other hand, at the transcriptional level, the addition of actinomycin D abolished the cAMP-mediated decrease in N-cadherin mRNA but did not change its stability. Inhibition of protein kinase A or expressing a dominant negative mutant of cAMP-response elementbinding protein blocked this decrease of N-cadherin mRNA. Together, the combined operation of post-translational and transcriptional mechanisms suggests that regulation of N-cadherin is a crucial event and emphasizes the important role that N-cadherin has in controlling the survival capability of human OSE.The surface of the human ovary is covered with a single layer of flat-to-cuboidal mesothelial cells, the ovarian surface epithelium (OSE).1 During each reproductive cycle, the OSE takes part in the cyclical ovulatory ruptures and repair. OSE on the preovulatory follicle undergoes apoptosis at the time of ovulation and then proliferates rapidly to repair the ruptured follicle and reconstitutes an intact mesothelium (1). However, factors regulating cell death and growth in human OSE are poorly understood. Because OSE is the source of epithelial ovarian carcinomas, which is the leading cause of death among all the human gynecological neoplasms, understanding the mechanisms that regulate OSE cell survival, apoptosis, and cell growth is of great clinical importance because an aberrant signaling of any of these pathways is likely to be involved in epithelial ovarian cancer. The cadherins are a family of cell surface glycoproteins that function in promoting calcium-dependent cell-cell adhesion and play crucial roles in the maintenance of structure, differentiation, and function of reproductive tissues (reviewed in Ref. 2). In general, cadherins are expressed in a cell-specific manner within specific compartments of the ovary, and their expression shows changes during different differentiation or...

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Section: Inhibitor Of Matrix Metalloproteinase Inhibits the Camp-medimentioning

confidence: 99%

Section: Inhibitor Of Matrix Metalloproteinase Inhibits the Camp-medimentioning

confidence: 99%

Gonadotropins Regulate N-cadherin-mediated Human Ovarian Surface Epithelial Cell Survival at Both Post-translational and Transcriptional Levels through a Cyclic AMP/Protein Kinase A Pathway

Pon

Auersperg

Wong

2005

Journal of Biological Chemistry

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“…Cells were seeded in 96-well plates at a density of 2x10 6 cells/well and incubated for 24 h. After treatment of drugs, the cell growth was assessed by staining with MTT dye at 37˚C for 2 h. The staining medium was then replaced by phosphate-buffered saline (PBS) with 2.5% of protamin sulfate stock solution (Sigma), and the plates were incubated at 4˚C overnight. The formazan was extracted with 250 µl of dimethyl sulfoxide (DMSO, 10%, Sigma) at room temperature for 4 h. Then 150 µl of the extract was transferred to a flat-bottomed 96-well plate for reading the absorbance at 570 nm in a microplate reader (Dynatech, UK).…”

Section: Methodsmentioning

confidence: 99%

“…Progesterone has strong effects on human hormone-responsive endometrial and breast cancers. It has also been reported that progesterone significantly inhibits cell proliferation and reduces the risk of ovarian carcinoma (6). In particular, because progesterone has been reported to have antiproliferative and apoptotic effects on ovarian cancer cell lines, progesterone has been widely used in the clinical treatment of ovarian carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Effect of combined treatment with progesterone and tamoxifen on the growth and apoptosis of human ovarian cancer cells

et al. 2011

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Abstract. Progesterone has a potential protective effect against ovarian carcinoma induced by estrogen. Progesterone is also known to cause apoptosis while tamoxifen induces growth arrest. Therefore, we attempted to determine whether combined treatment with progesterone and tamoxifen has a synergistic effect on anti-cancer activity. Although progesterone is known to cause apoptosis while tamoxifen induces growth arrest in many cancer cells, the detailed action of progesterone and tamoxifen and the anticancer effect of combined treatment have not been tested in ovarian cancer cells. Therefore, we tested the growth and apoptosis activity of progesterone and tamoxifen and the anticancer effect of combined treatment of progesterone and tamoxifen in ovarian cancer cells. Ovarian cancer cells, PA-1, were treated with progesterone, tamoxifen, or a combination of progesterone and tamoxifen. The anti-cancer effects were investigated by use of flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, DNA fragmentation analysis, and Western blot analysis. We found that 100 µM progesterone induced typical apoptosis in PA-1 cells. Treatment of PA-1 cells with 10 µM tamoxifen resulted in an increase in the levels of p21, p27, p16 and phospho-pRb, indicating typical G 1 arrest. Co-treatment of PA-1 cells with 100 µM progesterone and 10 µM tamoxifen resulted in typical apoptosis, similar to that induced by treatment with 100 µM progesterone alone. These results indicate that progesterone caused apoptosis and tamoxifen induced G 1 arrest. Combined treatment with tamoxifen and progesterone caused apoptosis similar to that induced by treatment with progesterone alone and had no additional anti-cancer effect in ovarian cancer cells.

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“…Though the role of ER in Lau's work was uncertain, others assert that the ER receptor subtype promotes apoptosis in OSE (Bardin et al, 2004). While estrogen has an unclear effect on cellular proliferation in OSE, progestins have a consistent effect of inhibiting cell growth and inflammation, and promoting apoptosis (Ivarsson et al, 2001;Karlan et al, 1995;Rae et al, 2004a). In vivo, macaques treated with progestin exhibited upregulation of apoptosis in OSE cells (Rodriguez et al, 1998).…”

Section: Estrogen and Progesterone Signaling In Normal Ovarian Surfacmentioning

confidence: 99%

Steroid Hormones and Ovarian Cancer

King¹,

Wong²

2011

Steroids - Clinical Aspect

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Production of Steroids by Human Ovarian Surface Epithelial Cells in Culture: Possible Role of Progesterone as Growth Inhibitor

Cited by 54 publications

References 31 publications

Gonadotropins Regulate N-cadherin-mediated Human Ovarian Surface Epithelial Cell Survival at Both Post-translational and Transcriptional Levels through a Cyclic AMP/Protein Kinase A Pathway

Gonadotropins Regulate N-cadherin-mediated Human Ovarian Surface Epithelial Cell Survival at Both Post-translational and Transcriptional Levels through a Cyclic AMP/Protein Kinase A Pathway

Effect of combined treatment with progesterone and tamoxifen on the growth and apoptosis of human ovarian cancer cells

Steroid Hormones and Ovarian Cancer

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