Selective killing of K-ras–transformed pancreatic cancer cells by targeting NADPH oxidaseReport as inadecuate




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Chinese Journal of Cancer

, 34:8

First Online: 08 April 2015Received: 17 August 2014Accepted: 22 December 2014DOI: 10.1186-s40880-015-0012-z

Cite this article as: Wang, P., Sun, YC., Lu, WH. et al. Chin J Cancer 2015 34: 8. doi:10.1186-s40880-015-0012-z

Abstract

IntroductionOncogenic 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.

MethodsROS level, NADPH oxidase NOX activity and expression, and cell invasion were examined in human pancreatic duct epithelial E6E7 cells transfected with K-ras compared with parental E6E7 cells. The cytotoxic effect and antitumor effect of capsaicin, a NOX inhibitor, were also tested in vitro and in vivo.

ResultsK-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.

ConclusionsK-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.

KeywordsK-ras Pancreatic cancer Reactive oxygen species NADPH oxidase Capsaicin Peng Wang and Yi-Chen Sun contributed equally to this work.

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

Source: https://link.springer.com/



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