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J. Biol. Chem., Vol. 280, Issue 15, 15438-15448, April 15, 2005

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Gonadotropins Regulate N-cadherin-mediated Human Ovarian Surface Epithelial Cell Survival at Both Post-translational and Transcriptional Levels through a Cyclic AMP/Protein Kinase A Pathway^*

Yuen Lam Pon, Nelly Auersperg, and Alice S. T. Wong¶

From the Department of Zoology, University of Hong Kong, Hong Kong and the Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia V6H 3V5, Canada

Gonadotropins are the major regulators of ovarian function and may be involved in the etiology of ovarian cancer. In this study, we report a new mechanism whereby gonadotropins regulate the survival of human ovarian surface epithelium (OSE), the tissue of origin of epithelial ovarian carcinomas. Our results indicate that disruption of N-cadherin-mediated cell-cell adhesion is an important molecular event in the apoptosis of human OSE. Treatment with surge serum concentrations of gonadotropins reduced the amount of N-cadherin with a concomitant induction of apoptosis, and this effect was mediated by a cAMP/protein kinase A pathway but not the ERK1/2 and protein kinase C cascades. We further demonstrated that activation of the gonadotropins/cAMP signaling pathway in human OSE led to a rapid down-regulation of N-cadherin protein level followed by a reduction at the level of N-cadherin mRNA, indicating that expression of N-cadherin was regulated by post-translational and transcriptional mechanisms. The former mechanism was mediated by increased turnover of N-cadherin protein and could be reversed by inhibition of proteasomal or matrix metalloproteinase (MMP-2) activity. On the other hand, at the transcriptional level, the addition of actinomycin D abolished the cAMP-mediated decrease in N-cadherin mRNA but did not change its stability. Inhibition of protein kinase A or expressing a dominant negative mutant of cAMP-response element-binding protein blocked this decrease of N-cadherin mRNA. Together, the combined operation of post-translational and transcriptional mechanisms suggests that regulation of N-cadherin is a crucial event and emphasizes the important role that N-cadherin has in controlling the survival capability of human OSE.

Received for publication, September 20, 2004 , and in revised form, February 1, 2005.

^* This work was supported by the Committee on Research and Conference Council Grant and RGC HKU 7484/04M (to A. S. T. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: 4S-14 Kadoorie Biological Sciences Bldg., Dept. of Zoology, University of Hong Kong, Pokfulam Rd., Hong Kong. Tel.: 852-2299-0865; Fax: 852-2559-9114; E-mail: awong1{at}hku.hk.

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