title: P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin.
abstract: Gonadotropin-releasing hormone (GnRH) is a potent prometastatic factor in ovarian cancer, but the intracellular signaling events are not well understood. The classical Gα(q)-phospholipase C signal transduction pathway known to operate in the pituitary is not involved in GnRH actions at non-pituitary targets. Here we showed that GnRH treatment of ovarian cancer cells led to a rapid and remarkable tyrosine phosphorylation of p120 catenin (p120(ctn)), which was mediated by P-cadherin. The use of P-cadherin small interfering RNA or neutralizing antibodies to inhibit P-cadherin expression and function resulted in diminished p120(ctn) activation, confirming that the effect was P-cadherin specific. On exploring how P-cadherin, which lacks intrinsic kinase activity, might regulate the activation of p120(ctn), we found that P-cadherin could induce the ligand-independent activation of insulin-like growth factor-1 receptor (IGF-1R). Inhibition of IGF-1R expression or its activity significantly inhibited GnRH-induced p120(ctn) activation, and the subsequent cell migration and invasion. In addition, we showed that IGF-1R regulation by P-cadherin was associated with complex formation between IGF-1R and P-cadherin, and this regulation was also observed to be in vivo correlated with metastasis. Furthermore, using a mouse model of ovarian cancer metastasis, GnRH receptor knockdown was shown to diminish peritoneal dissemination of tumors and ascites formation. These findings suggest for the first time that GnRH can initiate an outside-in p120(ctn) signal transduction through the cross-talk between P-cadherin and IGF-1R, thus providing a novel molecular mechanism by which GnRH may control the high level of aggressiveness and invasion and metastasis potential that are characteristic of ovarian cancer.
authors.affiliation: School of Biological Sciences, University of Hong Kong, Hong Kong, Hong Kong.
authors.forename: L W T
authors.initials: LW
authors.lastname: Cheung
authors.forename: A S C
authors.initials: AS
authors.lastname: Mak
authors.forename: A N Y
authors.initials: AN
authors.lastname: Cheung
authors.forename: H Y S
authors.initials: HY
authors.lastname: Ngan
authors.forename: P C K
authors.initials: PC
authors.lastname: Leung
authors.forename: A S T
authors.initials: AS
authors.lastname: Wong
mesh_terms: D000818:Animals; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D051177:Catenins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000095002:Delta Catenin
chemical_list: D015820:Cadherins; D051177:Catenins; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D017526:Receptor, IGF Type 1; D000095002:Delta Catenin