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.
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.
Pon
Yuen Lam
YL
Department of Zoology, University of Hong Kong, Hong Kong.
Auersperg
Nelly
N
Wong
Alice S T
AS
D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry*; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000737:chemistry; D004847:Epithelial Cells / Q000166:cytology*; D005260:Female; D006062:Gonadotropins / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D010053:Ovary / Q000378:metabolism*; D011419:Propidium / Q000737:chemistry; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012323:RNA Processing, Post-Transcriptional; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions; D013997:Time Factors; D014162:Transfection; D014343:Trypan Blue / Q000494:pharmacology
D017304:Annexin A5; D015820:Cadherins; D004396:Coloring Agents; D018076:DNA, Complementary; D006062:Gonadotropins; D011419:Propidium; D004533:Egtazic Acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D014343:Trypan Blue