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Selective killing of K-ras-transformed pancreatic cancer cells by targeting NAD(P)H oxidase
Peng Wang1,2, Yi-Chen Sun3, Wen-Hua Lu4
1Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, P.R. China. pengwangsysu@foxmail.com.
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.
Insights
K-ras oncogenic signaling in pancreatic cancer increases reactive oxygen species (ROS) via NADPH oxidase (NOX). Capsaicin, a NOX inhibitor, selectively targets and eliminates K-ras-transformed cells, offering a novel therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- K-ras gene mutations are prevalent in pancreatic ductal carcinoma, driving cancer development.
- Increased reactive oxygen species (ROS) are linked to various cancers, including pancreatic cancer.
Purpose of the Study:
- To investigate the link between K-ras-induced transformation and elevated ROS stress in pancreatic cancer.
- To explore the therapeutic potential of targeting ROS pathways in K-ras-driven pancreatic cancer.
Main Methods:
- Examined ROS levels, NADPH oxidase (NOX) activity, and cell invasion in K-ras-transfected pancreatic cells.
- Assessed the effects of capsaicin, a NOX inhibitor, on cell proliferation, invasion, and tumor growth in vitro and in vivo.
Main Results:
- K-ras transfection activated NOX, increasing ROS production via the PI3K pathway.
- Capsaicin inhibited NOX activity, leading to ROS accumulation and selective killing of K-ras-transformed cells.
- Capsaicin demonstrated antitumor effects in vivo, with oxidative damage to xenograft tumor cells.
Conclusions:
- K-ras oncogenic signaling elevates ROS through NOX activation.
- Abnormal ROS stress can be therapeutically exploited to selectively eliminate K-ras-transformed tumor cells.
- Targeting NOX with inhibitors presents a novel redox-mediated therapeutic strategy for K-ras-driven pancreatic cancer.
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