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Endocrinology Vol. 142, No. 2 580-588
Copyright © 2001 by The Endocrine Society

ARTICLES

Estradiol Regulates Gonadotropin-Releasing Hormone (GnRH) and its Receptor Gene Expression and Antagonizes the Growth Inhibitory Effects of GnRH in Human Ovarian Surface Epithelial and Ovarian Cancer Cells1

Sung Keun Kang2, Kyung-Chul Choi, Chen-Jei Tai, Nelly Auersperg and Peter C. K. Leung3

Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5

Address all correspondence and requests for reprints to: Peter C. K. Leung, Ph.D., Department of Obstetrics and Gynecology, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5. E-mail: peleung{at}interchange.ubc.ca

In the present study, we investigated the expression of estrogen receptors (ER{alpha} and ERß) in human ovarian surface epithelial (hOSE) cells and the ovarian cancer cell line, OVCAR-3, and provided novel evidence that estrogen may have a growth regulatory effect in these cells. Expression levels of ER{alpha} messenger RNA (mRNA) were 1.5-fold higher in OVCAR-3 cells than in hOSE cells, as revealed by semiquantitative RT-PCR and Southern blot analysis. A significant increase (3.3-fold) in ERß mRNA levels was observed in OVCAR-3 cells compared with hOSE cells. In parallel with mRNA levels, expression levels of ER{alpha} and ERß proteins were also higher in OVCAR-3 cells compared with hOSE cells. We recently proposed that GnRH and its receptor may have an autocrine role in hOSE and ovarian cancer cells. To determine whether estrogen regulates GnRH and GnRH receptor (GnRHR), hOSE and OVCAR-3 cells were treated with various concentrations of 17ß-estradiol for 24 h. Expression levels of GnRH and GnRHR mRNA were examined using quantitative and competitive RT-PCR, respectively. Treatment with 17ß-estradiol induced a significant down-regulation of GnRH mRNA in OVCAR-3 cells, but not in hOSE cells and of GnRHR mRNA in both hOSE and OVCAR-3 cells. Tamoxifen, an estrogen antagonist, prevented the effects of 17ßestradiol, suggesting that estradiol action is mediated via the ER. Finally, the effect of estrogen on the growth of hOSE and OVCAR-3 cells was investigated. The cells were treated with various concentrations of 17ß-estradiol, and the proliferative index of cells was measured using [3H]thymidine incorporation and DNA fluorometric assays. 17ß-Estradiol stimulated the growth of OVCAR-3 cells in a dose- and time-dependent manner. In contrast, 17ß-estradiol failed to stimulate the growth of hOSE cells. As estrogen down-regulated GnRH and GnRHR mRNA, we investigated whether estrogen treatment blocks the growth inhibitory effect of a GnRH agonist in OVCAR-3 and hOSE cells. Cells were treated with 17ß-estradiol (10-7 M) together with (D-Ala6)-GnRH (10-7 M), and the proliferative index of cells was measured. Pre- or cotreatment of cells with 17ß-estradiol significantly attenuated the growth inhibitory effect of the GnRH agonist in OVCAR-3 cells, whereas no effect of 17ß-estradiol treatment was observed in hOSE cells. To our knowledge, these results provide the first demonstration of a potential interaction between the estradiol/ER and GnRH/GnRHR systems, which may be important in the growth regulation of normal and neoplastic hOSE cells.




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