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RU486-Induced Growth Inhibition of Human Endometrial Cells Involves the Nuclear Factor-B Signaling Pathway

Division of Research, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia 30322

Address all correspondence and requests for reprints to: Neil Sidell, Ph.D., Department of Gynecology and Obstetrics, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, Georgia 30322. E-mail: nsidell{at}emory.edu.

Previous studies indicated that the antiprogestin RU486 could directly inhibit the growth of normal and malignant human endometrial cells. However, the mechanism by which this occurs is poorly understood. In this study we explore further details of endometrial cell growth regulation by RU486. Gel shift assays using the endometrial cell line EM42 demonstrated that RU486, at concentrations ranging from 20–100 µM, significantly stimulated the cellular binding activity of the nuclear transcription factor nuclear factor-B (NF-B) while having little effect on activating protein-1 (AP-1) binding. This effect on NF-B binding was blocked in the presence of the NF-B inhibitor, pyrrolidine dithiocarbamate (PDTC). The data also showed that the activity of RU486 on NF-B binding correlated with the ability of this compound to induce apoptosis of EM42 cells. To investigate a cause and effect relationship between these two phenomena, we evaluated the effects of RU486 treatment on the expression of two apoptosis-related genes, bax and bcl-2, known to be regulated through NF-B binding on their promoter. RT-PCR demonstrated that RU486 significantly induced bax mRNA levels, while suppressing mRNA of bcl-2. Alteration of these genes by RU486 was inhibited in the presence of 100 µM PDTC. Correspondingly, PDTC antagonized the ability of RU486 to inhibit the growth and induce apoptosis of EM42 cells. This study demonstrates that the inhibition of growth and apoptosis of human endometrial cells by RU486 involves stimulation of NF-B binding with subsequent modulation of apoptosis regulatory genes bax and bcl-2.

This work was supported by NIH Research Grant P01-HD-35276.

Abbreviations: AP-1, Activating protein-1; GAPDH, glyceraldehyde-3-phosphate-dehyrogenase; 13-HPODE, 13-hydroperoxide octadecadienoic acid; NF-B, nuclear factor-B; PDTC, pyrrolidine dithiocarbamate; PPAR, peroxisome proliferator-activated receptor-.

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