Abstract 1624: Black raspberries suppress phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway in carcinogen-induced esophageal cancer in rats
Authors: Yan Fei , Shen Na , Xu Zhenzhen , Nines Ronald G. , Edmonds Alexandria , Guan Huaji , Stoner Gary D. , Chen Tong 
Published: August 2012

Abstract
Esophageal squamous cell carcinoma (SCC) is one of the most common malignant neoplasms worldwide. The overall 5-year survival rate of esophageal SCC in the United States is only 13%, which is close to the observed rates in high-risk countries including China and other global regions. To decrease the incidence of esophageal cancer, cancer chemoprevention through dietary and/or chemical intervention would be a logical and practical approach. Our laboratory and others have used the N-nitrosomethylbenzylamine (NMBA)-induced rat preclinical model of esophageal cancer to investigate the mechanisms of esophageal carcinogenesis and to evaluate the efficacy of potential chemopreventive agents. Studies found that dietary freeze-dried black raspberries (BRBs) significantly inhibited NMBA-induced tumor development in rat esophagus, at least in part by inhibition of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)), c-Jun, vascular endothelial growth factor (VEGF), and activation of mitogen-activated protein kinase (MAPK) and nuclear factorβB (NFκB) pathways. The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays important roles in certain aspects of carcinogenesis. The principal objective of this study is to assess the roles of this signaling cascade in preclinical esophageal cancer model and examine the mechanistic actions of BRBs against this disease. In the present study, F344 rats were treated with NMBA (0.30 mg/kg b.w.) three times per week for 5 weeks. After 72 hours, animals were fed AIN-76A diet or AIN-76A diet containing 5% BRBs. At week 29, rats were sacrificed and esophageal tumors were counted. Western blot assays were conducted to detect the expression levels of some proteins involved in PI3K/AKT/mTOR pathway. Our data show that in esophageal preneoplastic lesions, BRBs significantly decreased expression levels of p-AKTSer478, p-PI3K-p83, p-S6 and p-mTORSer2448 from 3.2-fold, 5.9-fold, 5.4-fold and 4.4-fold in rats fed control diet to 0.9-fold (P &lt; 0.005), 1.1-fold (P &lt; 0.001), 1.2-fold (P &lt; 0.001) and 1.3-fold (P &lt; 0.001), in rats fed 5% BRBs, respectively. In papillomatous lesions, the expression levels of the above proteins were also reduced by BRBs from 5.3-fold to 1.5-fold (p-AKTSer478; P &lt; 0.001), 6.7-fold to 1.7-fold (p-PI3K-p83, P &lt; 0.001), 8.4-fold to 1.5-fold (p-S6, P &lt; 0.001) and 7.9-fold to 1.7-fold (p-mTORSer2448, P &lt; 0.001). Our results indicated that the PI3K/AKT/mTOR signaling pathway was activated in NMBA-induced tumor development in rats and the activation was significantly suppressed by BRBs. Further investigation of this signaling cascade in esophageal carcinogenesis is underway in our laboratory. (Supported by NCI RO1 CA131073-01A1).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1624. doi:1538-7445.AM2012-1624