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 bee...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.展开更多
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)
文摘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.
