NOX5-L can stimulate proliferation and apoptosis depending on its levels and cellular context, determining cancer cell susceptibility to cisplatin

So Hee Dho,Ki-Sun Kwon,Ji Young Kim,Sung Sup Park,Eun-Soo Kwon,Jae Cheong Lim

doi:10.18632/oncotarget.5743

Abstract

The NADPH oxidase, NOX5, is known to stimulate cell proliferation in some cancers by generating reactive oxygen species (ROS). We show here that the long form of NOX5 (NOX5-L) also promotes cell death, and thus determines the balance of proliferation and death, in skin, breast and lung cancer cells. Moderate expression of NOX5-L induced cell proliferation accompanied by AKT and ERK phosphorylation, whereas an increase in NOX5-L above a certain threshold promoted cancer cell death accompanied by caspase-3 activation. Notably, cisplatin treatment increased NOX5-L levels through CREB activation and enhanced NOX5-L activity through augmentation of Ca2+ release and c-Abl expression, ultimately triggering ROS-mediated cancer cell death-a distinct pathway absent in normal cells. These results indicate that NOX5-L determines cellular responses in a concentration- and context-dependent manner.

Highlights

Reactive oxygen species (ROS) were once considered detrimental cellular byproducts; they are widely accepted as signaling molecules that can determine whether cells proliferate or die [1, 2]
NOX5-L overexpression in WI-38 and MCF10A cells induced cell proliferation (Figure 1A) and resulted in production of ROS (Figure 1E). These findings suggest that generation of ROS by NOX5-L promotes cell proliferation
We examined the effect of NOX5-L expression on the activation of the main downstream effectors of tumorigenesis, AKT and ERK1/2, in normal cells

Summary

Introduction

Reactive oxygen species (ROS) were once considered detrimental cellular byproducts; they are widely accepted as signaling molecules that can determine whether cells proliferate or die [1, 2]. It is known that a high level of ROS can trigger cell death by mediating apoptosis through the c-Jun N-terminal kinase and p38 MAPK (mitogen-activated protein kinase) pathways [2, 3]. These pathways are activated by antineoplastic agents that elevate intracellular ROS [8, 9]. Members of the NADPH oxidase (NOX) family are the only enzymes that generate ROS as their main product [10] They reduce molecular oxygen in an NADPHdependent fashion to generate superoxide anion [11]. Considering the pleiotropic effects of ROS, NOX activity might contribute to cellular death as well as proliferation

Methods

Results

Conclusion