Suppression of Akt1-β-catenin pathway in advanced prostate cancer promotes TGFβ1-mediated epithelial to mesenchymal transition and metastasis

被引:25
作者
Gao, Fei [1 ,2 ,3 ]
Alwhaibi, Abdulrahman [1 ,2 ]
Sabbineni, Harika [1 ,2 ]
Verma, Arti [1 ,2 ]
Eldahshan, Wael [1 ,2 ]
Somanath, Payaningal R. [1 ,2 ,4 ,5 ]
机构
[1] Univ Georgia, Coll Pharm, Clin & Expt Therapeut, Augusta, GA 30912 USA
[2] Charlie Norwood VA Med Ctr, Augusta, GA 30912 USA
[3] Chongqing Med Univ, Affiliated Hosp 1, Dept Urol, Chongqing, Peoples R China
[4] Augusta Univ, Vasc Biol Ctr, Dept Med, Augusta, GA 30912 USA
[5] Augusta Univ, Ctr Canc, Augusta, GA 30912 USA
基金
美国国家卫生研究院; 中国国家自然科学基金;
关键词
Akt1; beta-catenin; Prostate cancer; Epithelial-to-mesenchymal transition; Metastasis; TGF-BETA; INTRAEPITHELIAL NEOPLASIA; MYOCARDIAL-INFARCTION; AKT ACTIVATION; CELL-MIGRATION; KINASE-B; EXPRESSION; GROWTH; CONSEQUENCES; TRICIRIBINE;
D O I
10.1016/j.canlet.2017.05.028
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:177 / 189
页数:13
相关论文
共 73 条
[1]   The Akt inhibitor, triciribine, ameliorates chronic hypoxia-induced vascular pruning and TGF-induced pulmonary fibrosis [J].
Abdalla, Maha ;
Sabbineni, Harika ;
Prakash, Roshini ;
Ergul, Adviye ;
Fagan, Susan C. ;
Somanath, Payaningal R. .
BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (16) :4173-4188
[2]   Akt1 Mediates α-Smooth Muscle Actin Expression and Myofibroblast Differentiation via Myocardin and Serum Response Factor [J].
Abdalla, Maha ;
Goc, Anna ;
Segar, Lakshman ;
Somanath, Payaningal R. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (46) :33483-33493
[3]   Delayed mammary gland involution in MMTV-AKT1 transgenic mice [J].
Ackler, S ;
Ahmad, S ;
Tobias, C ;
Johnson, MD ;
Glazer, RI .
ONCOGENE, 2002, 21 (02) :198-206
[4]   P21 activated kinase-1 mediates transforming growth factor β1-induced prostate cancer cell epithelial to mesenchymal transition [J].
Al-Azayzih, Ahmad ;
Gao, Fei ;
Somanath, Payaningal R. .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2015, 1853 (05) :1229-1239
[5]   TGFβ1 induces apoptosis in invasive prostate cancer and bladder cancer cells via Akt-independent, p38 MAPK and JNK/SAPK-mediated activation of caspases [J].
Al-Azayzih, Ahmad ;
Gao, Fei ;
Goc, Anna ;
Somanath, Payaningal R. .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2012, 427 (01) :165-170
[6]  
[Anonymous], BREAST CANC RES BCR
[7]  
[Anonymous], PROSTATE CANC PROSTA
[8]  
[Anonymous], J BIOL CHEM
[9]   Cadherins: The Superfamily Critically Involved in Breast Cancer [J].
Ashaie, Maeirah Afzal ;
Chowdhury, Ezharul Hoque .
CURRENT PHARMACEUTICAL DESIGN, 2016, 22 (05) :616-638
[10]   PTEN, more than the AKT pathway [J].
Blanco-Aparicio, Carmen ;
Renner, Oliver ;
Leal, Juan F. M. ;
Carnero, Amancio .
CARCINOGENESIS, 2007, 28 (07) :1379-1386