Gao Fei, Alwhaibi Abdulrahman, Sabbineni Harika, Verma Arti, Eldahshan Wael, Somanath Payaningal R
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA; Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA.
Cancer Lett. 2017 Aug 28;402:177-189. doi: 10.1016/j.canlet.2017.05.028. Epub 2017 Jun 7.
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 Snail1 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 TGFβ1 and its receptor TGFβ RII, associated with a decreased expression of β-catenin. Furthermore, treatment of PCa cells with ICG001 that blocks nuclear translocation of β-catenin promoted EMT and N-cadherin expression. Together, our study demonstrates a novel role of the Akt1-β-catenin-TGFβ1 pathway in advanced PCa.
Akt1在多种癌症的致癌转化和肿瘤生长中至关重要。然而，Akt1在晚期癌症中的确切作用存在争议。利用小鼠前列腺神经内分泌转基因腺癌（TRAMP）模型，我们首先表明，在小鼠中对Akt1进行基因敲除或药理抑制可抑制致癌转化和前列腺癌（PCa）生长。有趣的是，曲西立滨（TCBN）介导的对25周龄荷瘤TRAMP小鼠的Akt抑制以及在侵袭性PCa细胞中Akt1基因沉默增强了上皮-间质转化（EMT）并促进了肺转移。从机制上讲，Akt1抑制导致TRAMP前列腺以及PC3和DU145细胞中EMT标志物如Snail1和N-钙黏蛋白的表达增加，而上皮标志物E-钙黏蛋白的表达降低。接下来，我们发现PCa细胞中Akt1敲低导致TGFβ1及其受体TGFβ RII的产生增加，同时β-连环蛋白的表达降低。此外，用阻断β-连环蛋白核转位的ICG001处理PCa细胞可促进EMT和N-钙黏蛋白表达。总之，我们的研究证明了Akt1-β-连环蛋白-TGFβ1通路在晚期PCa中的新作用。
