E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing

Alterations in phosphatidylinositol 3-kinase (PI3K) and in PTEN (phosphatase and tensin homolog), the negative regulator of the PI3K pathway, are found in nearly half of human tumors. As PI3Kβ, the main isoform activated in PTEN-mutant tumors, has kinase-dependent and -independent activities, we com...

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Detalhes bibliográficos
Autores: Millán-Uclés, África, Zuluaga, Susana, Marqués, Marta, Vallejo-Díaz, Jesus, Sanz, Lorena, Cariaga-Martínez, Ariel E., Real, Francisco X., Carrera, Ana C.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Recursos:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/28360
Acesso em linha:http://hdl.handle.net/10230/28360
http://dx.doi.org/10.18632/oncotarget.13414
Access Level:acceso abierto
Palavra-chave:PI3Kbeta
PTEN
Urothelial carcinoma
Bladder cancer
SiRNA
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spelling E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencingMillán-Uclés, ÁfricaZuluaga, SusanaMarqués, MartaVallejo-Díaz, JesusSanz, LorenaCariaga-Martínez, Ariel E.Real, Francisco X.Carrera, Ana C.PI3KbetaPTENUrothelial carcinomaBladder cancerSiRNAAlterations in phosphatidylinositol 3-kinase (PI3K) and in PTEN (phosphatase and tensin homolog), the negative regulator of the PI3K pathway, are found in nearly half of human tumors. As PI3Kβ, the main isoform activated in PTEN-mutant tumors, has kinase-dependent and -independent activities, we compared the effects of depleting vs. drug-inhibiting PI3Kβ kinase activity in a collection of diverse tumor types and in a set of bladder carcinoma cell lines grown as xenografts in mice. PI3Kβ depletion (by intratumor injection of PIK3CB siRNA) induced apoptosis and triggered regression of PTEN-mutant tumors more efficiently than PI3Kβ inhibition. A small proportion of these tumors was resistant to PI3Kβ downregulation; we analyzed what determined resistance in these cases. Using add-back experiments, we show that both PTEN mutation and low E-cadherin expression are necessary for PI3Kβ dependence. In bladder carcinoma, loss of E-cadherin expression coincides with N-cadherin upregulation. We found that PI3Kβ associated with N-cadherin and that PIK3CB depletion selectively disrupted N-cadherin cell adhesions in PTEN-mutant bladder carcinoma. These results support the use of PIK3CB interfering RNA as a therapeutic approach for high-risk bladder cancers that show E-cadherin loss and express mutant PTEN.This work was financed by grants from the Spanish Ministry of Science and Innovation (SAF2011-29530 to FXR, SAF2013-48657 to ACC; Consolider ONCOBIO to FXR, Network of Cooperative Research in Cancer cofinanced by the European Regional Development Fund (RTICC RD12/0036/0059 to ACC and RD12/0036/0034 to FXR), the Madrid regional government (BMD2502 to ACC), and an AECC (Spanish Association against Cancer) grant to FXR.Impact Journals201720172016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/28360http://dx.doi.org/10.18632/oncotarget.13414reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésOncotarget. 2016;7:84054-71All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.https://creativecommons.org/licenses/by/3.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/283602026-06-12T07:21:37Z
dc.title.none.fl_str_mv E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing
title E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing
spellingShingle E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing
Millán-Uclés, África
PI3Kbeta
PTEN
Urothelial carcinoma
Bladder cancer
SiRNA
title_short E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing
title_full E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing
title_fullStr E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing
title_full_unstemmed E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing
title_sort E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing
dc.creator.none.fl_str_mv Millán-Uclés, África
Zuluaga, Susana
Marqués, Marta
Vallejo-Díaz, Jesus
Sanz, Lorena
Cariaga-Martínez, Ariel E.
Real, Francisco X.
Carrera, Ana C.
author Millán-Uclés, África
author_facet Millán-Uclés, África
Zuluaga, Susana
Marqués, Marta
Vallejo-Díaz, Jesus
Sanz, Lorena
Cariaga-Martínez, Ariel E.
Real, Francisco X.
Carrera, Ana C.
author_role author
author2 Zuluaga, Susana
Marqués, Marta
Vallejo-Díaz, Jesus
Sanz, Lorena
Cariaga-Martínez, Ariel E.
Real, Francisco X.
Carrera, Ana C.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PI3Kbeta
PTEN
Urothelial carcinoma
Bladder cancer
SiRNA
topic PI3Kbeta
PTEN
Urothelial carcinoma
Bladder cancer
SiRNA
description Alterations in phosphatidylinositol 3-kinase (PI3K) and in PTEN (phosphatase and tensin homolog), the negative regulator of the PI3K pathway, are found in nearly half of human tumors. As PI3Kβ, the main isoform activated in PTEN-mutant tumors, has kinase-dependent and -independent activities, we compared the effects of depleting vs. drug-inhibiting PI3Kβ kinase activity in a collection of diverse tumor types and in a set of bladder carcinoma cell lines grown as xenografts in mice. PI3Kβ depletion (by intratumor injection of PIK3CB siRNA) induced apoptosis and triggered regression of PTEN-mutant tumors more efficiently than PI3Kβ inhibition. A small proportion of these tumors was resistant to PI3Kβ downregulation; we analyzed what determined resistance in these cases. Using add-back experiments, we show that both PTEN mutation and low E-cadherin expression are necessary for PI3Kβ dependence. In bladder carcinoma, loss of E-cadherin expression coincides with N-cadherin upregulation. We found that PI3Kβ associated with N-cadherin and that PIK3CB depletion selectively disrupted N-cadherin cell adhesions in PTEN-mutant bladder carcinoma. These results support the use of PIK3CB interfering RNA as a therapeutic approach for high-risk bladder cancers that show E-cadherin loss and express mutant PTEN.
publishDate 2016
dc.date.none.fl_str_mv 2016
2017
2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/28360
http://dx.doi.org/10.18632/oncotarget.13414
url http://hdl.handle.net/10230/28360
http://dx.doi.org/10.18632/oncotarget.13414
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Oncotarget. 2016;7:84054-71
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/3.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/3.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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