Abstract
Akt1 is essential for the oncogenic transformation and tumor growth in various cancers. However, the precise role of Akt1 in advanced cancers is conflicting. Using a neuroendocrine TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, we first show that the genetic ablation or pharmacological inhibition of Akt1 in mice blunts oncogenic transformation and prostate cancer (PCa) growth. Intriguingly, triciribine (TCBN)-mediated Akt inhibition in 25-week old, tumor-bearing TRAMP mice and Akt1 gene silencing in aggressive PCa cells enhanced epithelial to mesenchymal transition (EMT) and promoted metastasis to the lungs. Mechanistically, Akt1 suppression leads to increased expression of EMT markers such as Snail] and N-cadherin and decreased expression of epithelial marker E-cadherin in TRAMP prostate, and in PC3 and DU145 cells. Next, we identified that Akt1 knockdown in PCa cells results in increased production of TGF beta 1 and its receptor TGF beta RII, associated with a decreased expression of beta-catenin. Furthermore, treatment of PCa cells with ICG001 that blocks nuclear translocation of beta-catenin promoted EMT and N-cadherin expression. Together, our study demonstrates a novel role of the Akt1-beta-catenin-TGF beta 1 pathway in advanced PCa. (C) 2017 Elsevier B.V. All rights reserved.