Selective killing of K-ras-transformed pancreatic cancer cells by targeting NAD(P)H oxidase  

作　　者：Peng Wang Yi-Chen Sun Wen-Hua Lu Peng Huang Yumin Hu 

机构地区：[1]Sun Yat-sen University Cancer Center [2]State Key Laboratory of Oncology in South China [3]Collaborative Innovation Center for Cancer Medicine [4]Institute of Cardiopulmonary Cerebral Resuscitation,Sun Yat-sen Memorial Hospital,Sun Yat-sen University [5]Department of Translational Molecular Pathology,The University of Texas MD Anderson Cancer Center

出　　处：《Chinese Journal of Cancer》2015年第4期166-176,共11页

基　　金：supported by research grants from the National Natural Science Foundation of China(No.81101520);the National Basic Research Program of China(973 program)(No.2013CB910304 and 2012CB967004)

摘　　要：Introduction:Oncogenic aaivation of the K-ras gene occurs in >90%of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy.Increase of reactive oxygen species(ROS) has also been observed in a wide spectrum of cancers.This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer.Methods:ROS level,NADPH oxidase(NOX) aaivity and expression,and cell invasion were examined in human pancreatic dua epithelial E6E7 cells transfeaed with K-ras^(G12V) compared with parental E6E7 cells.The cytotoxic effea and antitumor effect of capsaicin,a NOX inhibitor,were also tested in vitro and in vivo.Results:K-ras transfeaion caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3'-kinase(PI3K) pathway.Importantly,capsaicin preferentially inhibited the enzyme aaivity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells.Furthermore,capsaicin effeaively inhibited cell proliferation,prevented invasiveness of /(-ras-transformed pancreatic cancer cells,and caused minimum toxicity to parental E6E7 cells.In vivo,capsaicin exhibited antitumor aaivity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells.Conclusions:K-ras oncogenic signaling causes increased ROS stress through NOX,and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors.Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism.Introduction： Oncogenic activation of the K-rGs gene occurs in 〉90% of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy. Increase of reactive oxygen species （ROS） has also been observed in a wide spectrum of cancers. This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer. Methods： ROS level, NADPH oxidase （NOX） activity and expression, and cell invasion were examined in human pancreatic duct epithelial E6E7 cells transfected with K-FOSG12V compared with parental E6E7 cells. The cytotoxic effect and antitumor effect of capsaicin, a NOX inhibitor, were also tested in vitro and in vivo. Results： K-ras transfection caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositot 3＇-kinase （PI3K） pathway, Importantly, capsaicin preferentially inhibited the enzyme activity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells. Furthermore, capsaicin effectively inhibited cell proliferation, prevented invasiveness of K-ras-transformed pancreatic cancer cells, and caused minimum toxicity to parental E6E7 cells. In vivo, capsaicin exhibited antitumor activity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells. Conclusions： K-ras oncogenic signaling causes increased ROS stress through NOX, and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors. Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism.

关 键 词：NAD(P)H氧化酶 基因转化 癌细胞 胰腺癌 NADPH氧化酶 氧化还原酶 抗肿瘤活性 杀伤 

分 类 号：R735.9[医药卫生—肿瘤]