Regulation of Fas Ligand Expression By Estrogen in Normal Ovary

Sapi, Eva; Brown, Wendi; Aschkenazi, Sarit; Lim, Chung Thong; Muñoz, Amanda; Kacinski, Barry M.; Rutherford, Thomas J.; Mor, Gil

doi:10.1177/107155760200900411

Cited by 32 publications

(11 citation statements)

References 39 publications

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“…It has been shown that the ratio of FasL to Fas plays a very important role in tumor progression (Pinkoski and Green 2000;Reimer et al, 2000;Wajant, 2002). Other recent reports pertinent to our findings include a recent demonstration of upregulation of FasL expression in normal ovarian epithelium by estrogen (Sapi et al, 2002) and in vivo increased FasL and Fas expression in malignant and borderline ovarian tumors (van HaaftenDay et al, 2003).…”

Section: Discussionmentioning

confidence: 51%

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

Syed

2003

Oncogene

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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.

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Section: Discussionmentioning

confidence: 51%

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

Syed

2003

Oncogene

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“…Interestingly, in the female, strong FasL expression occurs in the endometrium in estrogen-dependent late proliferative and secretory phases (49). Additionally, in female rats, expression of FasL protein and mRNA levels in ovarian cell increases upon estrogen treatment (50). Therefore, our study shows for the first time that, in males as well, estrogen can induce expression of Fas-FasL system in the spermatogenic cells.…”

Section: Discussionmentioning

confidence: 68%

Diethylstilbestrol Induces Rat Spermatogenic Cell Apoptosis in Vivo through Increased Expression of Spermatogenic Cell Fas/FasL System

Nair

Shaha

2003

Journal of Biological Chemistry

106

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The significant role that estrogens play in spermatogenesis has opened up an exciting area of research in male reproductive biology. The realization that estrogens are essential for proper maintenance of spermatogenesis, as well as growing evidence pointing to the deleterious effects of estrogen-like chemicals on male reproductive health, has made it imperative to dissect the role estrogens play in the male. Using a model estrogen, diethylstilbestrol (DES), to induce spermatogenic cell apoptosis in vivo in the male rat, we provide a new insight into an estrogen-dependent regulation of the Fas-FasL system specifically in spermatogenic cells. We show a distinct increase in Fas-FasL expression in spermatogenic cells upon exposure to diethylstilbestrol. This increase is confined to the spermatid population, which correlates with increased apoptosis seen in the haploid cells. Testosterone supplementation is able to prevent DES-induced Fas-FasL up-regulation and apoptosis in the spermatogenic cells. DES-induced germ cell apoptosis does not occur in Fas-deficient lpr mice. One other important finding is that spermatogenic cells are type II cells, as the increase in Fas-FasL expression in the spermatogenic cells is followed by the cleavage of caspase-8 to its active form, following which Bax translocates to the mitochondria and precipitates the release of cytochrome c that is accompanied by a drop in mitochondrial potential. Subsequent to this, activation of caspase-9 occurs that in turn activates caspase-3 leading to the cleavage of poly(ADP-ribose) polymerase. Taken together, the data indicate that estrogen-like chemicals can precipitate apoptotic death in spermatogenic cells by increasing the expression of spermatogenic cell FasFasL, thus initiating apoptosis in the same lineage of cells through the activation of the apoptotic pathway chosen by type II cells.

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“…We have shown that the expression of Fas and FasL, in normal tissues, responds to the cyclic hormonal changes and that the apoptotic pathway is activated as a result of hormone withdrawal or decrease in estrogen and progesterone (Song et al, 2000(Song et al, , 2002Sapi et al, 2002). In this way, the Fas/FasL system controls cell number in the reproductive tissues by eliminating cells through apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…The Fas pathway is one of the main pathways mediating tissue remodelling in reproductive organs, including the mammary gland and the ovaries (Mori et al, 1997;Quirk et al, 1997;Song et al, 2000;Sapi et al, 2002). We have shown that the expression of Fas and FasL, in normal tissues, responds to the cyclic hormonal changes and that the apoptotic pathway is activated as a result of hormone withdrawal or decrease in estrogen and progesterone (Song et al, 2000(Song et al, , 2002Sapi et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Phenoxodiol – an isoflavone analog – induces apoptosis in chemoresistant ovarian cancer cells

et al. 2003

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Interference with the innate apoptotic activity is a hallmark of neoplastic transformation and tumor formation. In this study we characterize the cytotoxic effect of phenoxodiol, a synthetic anticancer drug analog of genestein, and demonstrate the mechanism of action by which phenoxodiol affects the components of the Fas apoptotic pathway on ovarian cancer cells. Primary ovarian cancer cells, isolated from ascitic fluids of ovarian cancer patients, resistant to conventional chemotherapy, undergo apoptosis following phenoxodiol treatment. This effect is dependent upon the activation of the caspase system, inhibiting XIAP, an inhibitor of apoptosis, and disrupting FLICE inhibitory protein (FLIP) expression through the Akt signal transduction pathway. We suggest that phenoxodiol is an efficient inducer of cell death in ovarian cancer cells and sensitizes the cancer cells to Fasmediated apoptosis. We identified FLIP and XIAP signalling pathways as key factors regulating the survival of ovarian cancer cells. These findings demonstrate a novel nontoxic drug that controls FLIP/XIAP function and has the potential to eliminate tumor cells through Fasmediated apoptosis.

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Regulation of Fas Ligand Expression By Estrogen in Normal Ovary

Abstract: Our findings support the hypothesis that the expression of FasL in normal ovary is hormonally sensitive and could have a key role in the physiology of normal ovarian tissue.

Cited by 32 publications

References 39 publications

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

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

Diethylstilbestrol Induces Rat Spermatogenic Cell Apoptosis in Vivo through Increased Expression of Spermatogenic Cell Fas/FasL System

Phenoxodiol – an isoflavone analog – induces apoptosis in chemoresistant ovarian cancer cells

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