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

Millán-Uclés, África; Zuluaga, Susana; Marqués, Marta; Vallejo-Díaz, Jesus; Sanz, Lorena; Cariaga-Martínez, Ariel E.; Real, Francisco X.; Carrera, Ana C.

doi:http://dx.doi.org/10.18632/oncotarget.13414

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

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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

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.