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

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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, HOSE 12-12) and two malignant (OVCA 429, OVCA 432) HOSE cell lines. The exposure of HOSE or OVCA cell cultures to 10−6 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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Acknowledgements

This study was supported by an Army Ovarian Cancer Research Program Grant DAMD17-99-1-9563 (to S-M Ho) and NIH Grants CA091250 (to V Syed) and CA94221 (to S-M Ho). This publication was made possible by Grant Number 5 P30 DK32520 from the National Institute of Diabetes and Digestive and Kidney Diseases'. We thank Dr Samuel C Mok of Brigham and Women's Hospital, Boston, Massachusetts, for his generous gifts of HOSE and OVCA cell lines and editorial staff of Brigham and Women's Hospital, Boston, for editorial help.

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  1. Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA

    Viqar Syed & Shuk-Mei Ho

  2. Department of Cell Biology and Physiology, University of Massachusetts Medical School, Worcester, MA, USA

    Shuk-Mei Ho

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  1. Viqar Syed
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  2. Shuk-Mei Ho
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Correspondence to Shuk-Mei Ho.

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Syed, V., Ho, SM. Progesterone-induced apoptosis in immortalized normal and malignant human ovarian surface epithelial cells involves enhanced expression of FasL. Oncogene 22, 6883–6890 (2003). https://doi.org/10.1038/sj.onc.1206828

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  • DOI: https://doi.org/10.1038/sj.onc.1206828

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