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,Jincai Hou,Cheng Zeng,Zhicheng Yang,Cuixiang Zhang,Bing Liu,Min Zhang,Jianxun Liu

doi:10.18632/oncotarget.2671

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.

Highlights

Chronic inflammation is induced by a variety of pathogenic and environmental factors and is associated with an increased risk of several human cancers [1]
As a previous study indicates that NADPH oxidase 4 (NOX4) mediates hypoxiainduced IL-6 production in renal cell carcinoma cells [18], we sought to the possible correlation of NOX4 and IL-6 expression levels in non-small cell lung cancer (NSCLC)
We found that exogenous IL-6 treatment could stimulate STAT3 activity in NSCLC cells via activation of JAK

Summary

INTRODUCTION

Chronic inflammation is induced by a variety of pathogenic and environmental factors and is associated with an increased risk of several human cancers [1]. Inflammatory cells in the tumor microenvironment may release cytokines to directly stimulate oncogenic signaling in cancer cells, including NF-κB, STAT3 and HIF1α signalings, resultantly promoting cancer survival and proliferation [5]. ROS have been reported to promote tumor cell survival and growth through activation of various signal pathways in cancer cells [7, 8]. Many studies including ours have confirmed the close correlation of NOXs with cancer cell growth and malignant progression [11,12,13]. The molecular mechanisms underlying the associations among microenvironmental cytokines, ROS production in tumor cells and cancer promotion are not well defined. Human recombined IL-6 treatment could significantly enhance NOX4 expression and ROS production 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

RESULTS

DISCUSSION

MATERIAL AND METHODS