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Article: P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin

TitleP-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin
Authors
KeywordsGnRH
IGF-1R
motility
ovarian cancer
P-cadherin
p120ctn
Issue Date2011
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2011, v. 30 n. 26, p. 2964-2974 How to Cite?
AbstractGonadotropin-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. © 2011 Macmillan Publishers Limited All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/135673
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grant Council778108
HKU
Funding Information:

We thank Dr N Auersperg for cell lines. This work was supported by Hong Kong Research Grant Council 778108 and HKU Outstanding Young Researcher Award (AST Wong).

References

 

DC FieldValueLanguage
dc.contributor.authorCheung, LWTen_HK
dc.contributor.authorMak, ASCen_HK
dc.contributor.authorCheung, ANYen_HK
dc.contributor.authorNgan, HYSen_HK
dc.contributor.authorLeung, PCKen_HK
dc.contributor.authorWong, ASTen_HK
dc.date.accessioned2011-07-27T01:39:11Z-
dc.date.available2011-07-27T01:39:11Z-
dc.date.issued2011en_HK
dc.identifier.citationOncogene, 2011, v. 30 n. 26, p. 2964-2974en_HK
dc.identifier.issn0950-9232en_HK
dc.identifier.urihttp://hdl.handle.net/10722/135673-
dc.description.abstractGonadotropin-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. © 2011 Macmillan Publishers Limited All rights reserved.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_HK
dc.relation.ispartofOncogeneen_HK
dc.subjectGnRHen_HK
dc.subjectIGF-1Ren_HK
dc.subjectmotilityen_HK
dc.subjectovarian canceren_HK
dc.subjectP-cadherinen_HK
dc.subjectp120ctnen_HK
dc.subject.meshCadherins - antagonists and inhibitors - genetics - physiology-
dc.subject.meshCarcinoma - genetics - pathology-
dc.subject.meshCatenins - genetics - metabolism - physiology-
dc.subject.meshOvarian Neoplasms - genetics - pathology-
dc.subject.meshReceptor, IGF Type 1 - antagonists and inhibitors - genetics - physiology-
dc.titleP-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 cateninen_HK
dc.typeArticleen_HK
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hken_HK
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hken_HK
dc.identifier.emailWong, AST: awong1@hkucc.hku.hken_HK
dc.identifier.authorityCheung, ANY=rp00542en_HK
dc.identifier.authorityNgan, HYS=rp00346en_HK
dc.identifier.authorityWong, AST=rp00805en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/onc.2011.7en_HK
dc.identifier.pmid21317933-
dc.identifier.scopuseid_2-s2.0-79959850623en_HK
dc.identifier.hkuros186752en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79959850623&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume30en_HK
dc.identifier.issue26en_HK
dc.identifier.spage2964en_HK
dc.identifier.epage2974en_HK
dc.identifier.eissn1476-5594-
dc.identifier.isiWOS:000292245100007-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridCheung, LWT=14119560800en_HK
dc.identifier.scopusauthoridMak, ASC=7103123348en_HK
dc.identifier.scopusauthoridCheung, ANY=54927484100en_HK
dc.identifier.scopusauthoridNgan, HYS=34571944100en_HK
dc.identifier.scopusauthoridLeung, PCK=12782513900en_HK
dc.identifier.scopusauthoridWong, AST=23987963300en_HK
dc.identifier.citeulike8845954-

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