E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing
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- dc.contributor.author Millán-Uclés, Áfricaca
- dc.contributor.author Zuluaga, Susanaca
- dc.contributor.author Marqués, Martaca
- dc.contributor.author Vallejo-Díaz, Jesusca
- dc.contributor.author Sanz, Lorenaca
- dc.contributor.author Cariaga-Martínez, Ariel E.ca
- dc.contributor.author Real, Francisco X.ca
- dc.contributor.author Carrera, Ana C.ca
- dc.date.accessioned 2017-03-31T10:45:21Z
- dc.date.available 2017-03-31T10:45:21Z
- dc.date.issued 2016
- dc.description.abstract 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.
- dc.description.sponsorship 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.
- dc.format.mimetype application/pdfca
- dc.identifier.citation Milán-Uclés A, Zuluaga S, Marqués M, Vallejo-Díaz J, Sanz L, Cariaga-Martínez AE et al. E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing. Oncotarget. 2016;7:84054-71. DOI: 10.18632/oncotarget.13414
- dc.identifier.doi http://dx.doi.org/10.18632/oncotarget.13414
- dc.identifier.issn 1949-2553
- dc.identifier.uri http://hdl.handle.net/10230/28360
- dc.language.iso eng
- dc.publisher Impact Journalsca
- dc.relation.ispartof Oncotarget. 2016;7:84054-71
- dc.rights All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri https://creativecommons.org/licenses/by/3.0/
- dc.subject.keyword PI3Kbeta
- dc.subject.keyword PTEN
- dc.subject.keyword Urothelial carcinoma
- dc.subject.keyword Bladder cancer
- dc.subject.keyword SiRNA
- dc.title E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencingca
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion