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Reciprocal activation between IL-6/STAT3 and NOX4/Akt signalings promotes proliferation and survival of non-small cell lung cancer cells

Juan Li _, Tian Lan, Cuixiang Zhang, Cheng Zeng, Jincai Hou, Zhicheng Yang, Min Zhang, Jianxun Liu and Bing Liu

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Oncotarget. 2015; 6:1031-1048. https://doi.org/10.18632/oncotarget.2671

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Juan Li1,*, Tian Lan2,*, Cuixiang Zhang3,4,*, Cheng Zeng1, Jincai Hou3,4, Zhicheng Yang5, Min Zhang6, Jianxun Liu3,4, Bing Liu1

1Clinical Pharmacy Department, Guangdong Pharmaceutical University, Guangzhou 510006, China

2Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China

3Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 110300, China

4Beijing Key Laboratory of Pharmacology of Chinese Materia Medica, Beijing 110300, China

5Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China

6Department of Health Statistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510006, China

*These authors contributed equally to this work

Correspondence to:

Bing Liu, e-mail: liubing52000@163.com

Keywords: NOX4, IL-6, non-small cell lung cancer, oxidative stress

Received: July 09, 2014     Accepted: November 02, 2014     Published: January 08, 2015


Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer. Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC). In our recent study, we confirmed that NADPH oxidase 4 (NOX4), an important source of reactive oxygen species (ROS) production in NSCLC cells, promotes malignant progression of NSCLC. However, whether the crosstalk of NOX4 and IL-6 signalings exists in NSCLC remains undentified. In this study, we show that NOX4 expression is positively correlated with IL-6 expression in NSCLC tissues. Exogenous IL-6 treatment significantly enhances NOX4/ROS/Akt signaling in NSCLC cells. NOX4 also enhances IL-6 production and activates IL-6/STAT3 signaling in NSCLC cells. Specifically, NOX4 is confirmed to functionally interplay with IL-6 to promote NSCLC cell proliferation and survival. The in vivo results were similar to those obtained in vitro. These data indicate a novel NOX4-dependent link among IL-6 in the NSCLC microenvironment, oxidative stress in NSCLC cells and autocrined IL-6 in NSCLC cells. NOX4/Akt and IL-6/STAT3 signalings can reciprocally and positively regulate each other, leading to enhanced NSCLC cell proliferation and survival. Therefore, NOX4 may serve as a promising target against NSCLC alone with IL-6 signaling.

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