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Selective killing of K-ras-transformed pancreatic cancer cells by targeting NAD(P)H oxidase / 癌症
Chinese Journal of Cancer ; (12): 166-176, 2015.
Article in English | WPRIM | ID: wpr-349605
ABSTRACT
<p><b>INTRODUCTION</b>Oncogenic activation 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.</p><p><b>METHODS</b>ROS level, NADPH oxidase (NOX) activity and expression, and cell invasion were examined in human pancreatic duct epithelial E6E7 cells transfected with K-ras (G12V) compared with parental E6E7 cells. The cytotoxic effect and antitumor effect of capsaicin, a NOX inhibitor, were also tested in vitro and in vivo.</p><p><b>RESULTS</b>K-ras transfection 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 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.</p><p><b>CONCLUSIONS</b>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.</p>
Subject(s)
Full text: Available Index: WPRIM (Western Pacific) Main subject: Pancreatic Neoplasms / Capsaicin / Transfection / Signal Transduction / Cell Transformation, Neoplastic / Genes, ras / Reactive Oxygen Species / NADPH Oxidases / Phosphatidylinositol 3-Kinases / Carcinoma, Pancreatic Ductal Limits: Humans Language: English Journal: Chinese Journal of Cancer Year: 2015 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: Pancreatic Neoplasms / Capsaicin / Transfection / Signal Transduction / Cell Transformation, Neoplastic / Genes, ras / Reactive Oxygen Species / NADPH Oxidases / Phosphatidylinositol 3-Kinases / Carcinoma, Pancreatic Ductal Limits: Humans Language: English Journal: Chinese Journal of Cancer Year: 2015 Type: Article