Progesterone-induced apoptosis in immortalized normal and malignant human ovarian surface epithelial cells involves enhanced expression of FasL

Abstract

Progesterone (P4) has been implicated as a protective factor for epithelial ovarian cancers, yet little is known about its mechanism of action. We previously reported that pregnancy-equivalent doses of P4 inhibited the growth of normal and malignant human ovarian surface epithelial (HOSE) cells. Here, we investigated how P4-induced cell death in two immortalized normal (HOSE 642, and two malignant (OVCA 429, OVCA 432) HOSE cell lines. The exposure of HOSE or OVCA cell cultures to 10 À6 m P4 induced time-dependent increases in early and late apoptotic cells and activation of caspase-8 and -3, but not that of caspase-9. A general caspase inhibitor Z-VAD effectively blocked the P4-induced cell death in a dose-dependent manner. Comparable levels of Fas mRNA and protein were expressed in HOSE and OVCA cell lines, and these levels were unaffected by P4. In contrast, levels of FasL mRNA and protein were higher in OVCA cells than in HOSE cells. Interestingly, the hormone enhanced levels of FasL mRNA and protein in HOSE cells, but lowered their levels in OVCA cells. The exposure of HOSE or OVCA cells to an activating anti-Fas antibody induced cell loss, whereas treatment of cells with a blocking anti-FasL antibody reduced the P4-induced cell loss. Cotreatment of cells with the activating anti-Fas antibody and P4 produced additive effects on cell loss. These results reveal for the first time that P4 induces apoptosis in HOSE and OVCA cells via activation of a caspase-8-initiated Fas/ FasL signaling pathway. They also demonstrate differential P4-regulation of FasL expression between HOSE and OVCA cells.

The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitro

“…First, EDD plays a pivotal role in the progesterone pathway, being both regulated by progestin and directly binding the progestin receptor and enhancing its transcriptional activity (Callaghan et al, 1998;Henderson et al, 2002). It has been known for several years that progesterone has a protective effect on ovarian cancer, the mechanism attributed to a reversal of the transformed phenotype including reduction of cyclin-dependent kinase activity and increased Fas/FasL-induced apoptosis (Blumenthal et al, 2003;Syed and Ho, 2003).…”

Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling

“…We have previously described the origin and culture conditions of nontumorigenic human OSE cell lines (HOSEs) and OCa cell lines (OVCAs) used in this study (Syed et al, 2001(Syed et al, , 2002Syed and Ho, 2003). In short, three HOSE cell lines (HOSE 642, were derived from normal ovaries obtained from women with noncancer gynecologic indications, specifically a 46-year-old healthy woman, a 48-year-old with ovarian inclusion cysts in one ovary, and a 39-year-old patient with ovarian stromal hyperplasia, respectively.…”

“…A handful of studies have demonstrated that progestins inhibit cell growth and/or induce apoptosis in OCa cell cultures (Bu et al, 1997;Hu and Deng, 2000;Keith and Bonavida, 2001;Yu et al, 2001;Syed and Ho, 2003). Alterations in apoptosis regulators such as bcl-2, c-myc, and p53 were detected in OCa cells undergoing progestin-induced apoptosis (Bu et al, 1997;Hu and Deng, 2000;Athanassiadou et al, 1998).…”

Steroid Hormones and Ovarian Cancer

“…In vivo, macaques treated with progestin exhibited upregulation of apoptosis in OSE cells (Rodriguez et al, 1998). Though the exact mechanism by which progesterone exhibits growth-inhibitory effects is not fullyunderstood, Syed and Ho (2003) demonstrated involvement of the caspase 8 Fas/FasL pathway in progesterone-mediated apoptosis in OSE. Culturing OSE in vitro with the inflammatory mediator IL-1 results in upregulation of several inflammation-associated genes, specifically HSD11B1, which plays a role in conversion of cortisone to cortisol (Rae et al, 2004b).…”