NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation.

Ildiko Szanto

doi:10.3390/ijms23052702

Abstract

Cancer cells can survive and maintain their high proliferation rate in spite of their hypoxic environment by deploying a variety of adaptative mechanisms, one of them being the reorientation of cellular metabolism. A key aspect of this metabolic rewiring is the promotion of the synthesis of antioxidant molecules in order to counter-balance the hypoxia-related elevation of reactive oxygen species (ROS) production and thus combat the onset of cellular oxidative stress. However, opposite to their negative role in the inception of oxidative stress, ROS are also key modulatory components of physiological cellular metabolism. One of the major physiological cellular ROS sources is the NADPH oxidase enzymes (NOX-es). Indeed, NOX-es produce ROS in a tightly regulated manner and control a variety of cellular processes. By contrast, pathologically elevated and unbridled NOX-derived ROS production is linked to diverse cancerogenic processes. In this respect, NOX4, one of the members of the NOX family enzymes, is of particular interest. In fact, NOX4 is closely linked to hypoxia-related signaling and is a regulator of diverse metabolic processes. Furthermore, NOX4 expression and function are altered in a variety of malignancies. The aim of this review is to provide a synopsis of our current knowledge concerning NOX4-related processes in the oncogenic metabolic adaptation of cancer cells.

Highlights

Cancer initiation, progression, and propagation are multifactorial and intertwined events
reactive oxygen species (ROS) modulate the rewiring of cellular metabolic pathways that are critical for cancer cell survival and proliferation [4–6]
One of the cellular ROS sources enticing emergent interest in these oncogenic processes is the family of NADPH oxidase enzymes (NOX-es) [10–12]

Summary

Introduction

Progression, and propagation are multifactorial and intertwined events. One of the cellular ROS sources enticing emergent interest in these oncogenic processes is the family of NADPH oxidase enzymes (NOX-es) [10–12]. A disruption of this coordinated NOX-derived ROS production is associated with multitudinous pathological alterations, among them cancerogenesis [10–12,15]. Elevated NOX4 mRNA and protein levels have been identified in cancers of diverse origins [10,20–27]. ETdhbisyrpeverieowxiassembles recent data on redox signaling in the adaptation of cancer cell metabolism with a specific focus on the role of NOX4 in these processes. The elimination H2O2 relies mainly on the glutathione and peroxiredoxin/thioredoxin systems that degrade H2O2 in a coordinated and cyclic manner through a series of oxidation/reduction reactions [63–65]. An i between the capacities of the cellular pro- and antioxidant systems will lead to di redox homeostasis and promote the onset of oxidative or reductive stress [69–73]. One of the cellular ROS sources whose perturbed functions have been related to oncogenesis is the family of NOX enzymes

The Family of NADPH Oxidase Enzymes

The NADPH Oxidase 4 (NOX4)

Findings

NOX4 as a Therapeutic Target in Cancers