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

INTRODUCTION: 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...

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Autores principales: Wang, Peng, Sun, Yi-Chen, Lu, Wen-Hua, Huang, Peng, Hu, Yumin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593348/
https://www.ncbi.nlm.nih.gov/pubmed/25963558
http://dx.doi.org/10.1186/s40880-015-0012-z
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author Wang, Peng
Sun, Yi-Chen
Lu, Wen-Hua
Huang, Peng
Hu, Yumin
author_facet Wang, Peng
Sun, Yi-Chen
Lu, Wen-Hua
Huang, Peng
Hu, Yumin
author_sort Wang, Peng
collection PubMed
description INTRODUCTION: 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. METHODS: 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. RESULTS: 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. 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.
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spelling pubmed-45933482015-10-06 Selective killing of K-ras–transformed pancreatic cancer cells by targeting NAD(P)H oxidase Wang, Peng Sun, Yi-Chen Lu, Wen-Hua Huang, Peng Hu, Yumin Chin J Cancer Original Article INTRODUCTION: 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. METHODS: 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. RESULTS: 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. 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. BioMed Central 2015-04-08 /pmc/articles/PMC4593348/ /pubmed/25963558 http://dx.doi.org/10.1186/s40880-015-0012-z Text en © Wang et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Original Article
Wang, Peng
Sun, Yi-Chen
Lu, Wen-Hua
Huang, Peng
Hu, Yumin
Selective killing of K-ras–transformed pancreatic cancer cells by targeting NAD(P)H oxidase
title Selective killing of K-ras–transformed pancreatic cancer cells by targeting NAD(P)H oxidase
title_full Selective killing of K-ras–transformed pancreatic cancer cells by targeting NAD(P)H oxidase
title_fullStr Selective killing of K-ras–transformed pancreatic cancer cells by targeting NAD(P)H oxidase
title_full_unstemmed Selective killing of K-ras–transformed pancreatic cancer cells by targeting NAD(P)H oxidase
title_short Selective killing of K-ras–transformed pancreatic cancer cells by targeting NAD(P)H oxidase
title_sort selective killing of k-ras–transformed pancreatic cancer cells by targeting nad(p)h oxidase
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593348/
https://www.ncbi.nlm.nih.gov/pubmed/25963558
http://dx.doi.org/10.1186/s40880-015-0012-z
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