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

// Juan Li 1, * , Tian Lan 2, * , Cuixiang Zhang 3, 4, * , Cheng Zeng 1 , Jincai Hou 3, 4 , Zhicheng Yang 5 , Min Zhang 6 , Jianxun Liu 3, 4 , Bing Liu 1 1 Clinical Pharmacy Department, Guangdong Pharmaceutical University, Guangzhou 510006, China 2 Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China 3 Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 110300, China 4 Beijing Key Laboratory of Pharmacology of Chinese Materia Medica, Beijing 110300, China 5 Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China 6 Department 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 ABSTRACT 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.