Activation of AKT Signaling Promotes Epithelial-Mesenchymal Transition and Tumor Growth in Colorectal Cancer Cells

被引:76
作者
Suman, Suman [1 ]
Kurisetty, Vittal [1 ]
Das, Trinath P. [1 ]
Vadodkar, Aditi [1 ]
Ramos, Gabriel [1 ]
Lakshmanaswamy, Rajkumar [1 ]
Damodaran, Chendil [1 ]
机构
[1] Texas Tech Univ Hlth Sci Ctr, Paul L Foster Sch Med, Dept Biomed Sci, El Paso, TX 79905 USA
关键词
AKT signaling; EMT; colon cancer; E-CADHERIN EXPRESSION; PROTEIN-KINASE; BETA-CATENIN; THERAPEUTIC TARGET; CELLULAR-SURVIVAL; KAPPA-B; METASTASIS; PATHWAY; ANGIOGENESIS; EMT;
D O I
10.1002/mc.22076
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Activation of the serine-threonine protein kinase AKT has emerged as a central feature of epithelial-mesenchymal transition (EMT), which is the initial step for metastasis in many cancer models, including colorectal cancer. The focus of our study was to dissect the role of AKT and its molecular regulation of EMT in colorectal cancer. HCT-116 colorectal cancer cells stably overexpressing AKT (AKT/HCT-116) showed significantly higher cell proliferation compared with vector-transfected cells (pCMV/HCT-116). Elevated expression of important EMT-related transcription factors and genes such as Snail, Slug, -catenin, vimentin, and MMP-9 correlated with increased migration and invasion by AKT/HCT-116 cells. Further, in vivo studies confirmed that AKT/HCT-116 xenografts were highly aggressive and angiogenic in nature compared with pCMV/HCT-116 xenografts. Molecular analysis of tumor samples revealed transcriptional regulation of Snail, Slug, -catenin, MMP-2, and MMP-9 in AKT/HCT-116 tumors. These results were supported by immunohistochemistry analysis. Low levels of E-cadherin expression with a concomitant increase in and nuclear localization of -catenin were evident in AKT/HCT-116 tumors compared with control tumors. Increased microvessel formation coincident with high expression of Factor VIII and increased numbers of reticulocytes confirmed the angiogenic property of AKT/HCT-116 tumors. Our results confirm the potential role of AKT signaling in regulating EMT and angiogenesis in colorectal cancer and suggest that inhibition of AKT can serve as an important therapeutic strategy in modulating EMT in colorectal cancer growth and metastasis. (c) 2013 Wiley Periodicals, Inc.
引用
收藏
页码:E151 / E160
页数:10
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