Aiding and abetting roles of NOX oxidases in cellular transformation

Abstract

NADPH oxidases of the NADPH oxidase (NOX) family are dedicated reactive oxygen species-generating enzymes that broadly and specifically regulate redox-sensitive signalling pathways that are involved in cancer development and progression. They act at specific cellular membranes and microdomains through the activation of oncogenes and the inactivation of tumour suppressor proteins. In this Review, we discuss primary targets and redox-linked signalling systems that are influenced by NOX-derived ROS, and the biological role of NOX oxidases in the aetiology of cancer.

Figure 1. Structure and molecular organization of the NADPH oxidases of the NOX family

Part a shows the topology and the enzymatic reaction catalysed by the NADPH oxidase (NOX) enzymes. Parts b–e represent the molecular structure of NOX2, NOX1, NOX4 and NOX5, which are predominantly expressed in carcinoma cells. All NOX proteins can form a complex with p22phox, but the cytosolic subunits differ between the NOX oxidase isoforms. e, electron; FAD, flavin, superoxide; POLDIP2, DNA polymerase-δ-interacting adenine dinucleotide; H, Haem; H₂O₂, hydrogen peroxide; O₂ protein 2; TKS, tyrosine kinase substrate.

Figure 2. Integration of NOX oxidase-derived ROS with the hallmarks of cancer

This figure shows the potential signalling pathways that are activated (+) or inactivated (−) by NADPH oxidase (NOX) oxidases and how they relate to some of the suggested hallmarks of cancer cells, such as deregulated cell growth and angiogenesis. GPCRs, G protein-coupled receptors; HIFs, hypoxia-inducible factors; MMPs, matrix metalloproteinases; PPase, protein phosphatase; PTPs, protein tyrosine phosphatases; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; TSC2, tuberous sclerosis 2; VEGF, vascular endothelial growth factor.

Figure 3. A hypothesis for the function of NOX-derived ROS in the progression of carcinogenesis

Multiple genetic and epigenetic alterations (HITS) are required for cellular transformation. The cells that upregulate NADPH oxidase (NOX) oxidases and NOX-derived reactive oxygen species (ROS) will maintain unregulated cell growth, evade cell death and progress towards the development of a clinically relevant tumour. Cells that do not activate NOX-derived ROS and that have intact apoptotic pathways will undergo apoptosis or necrosis. In tumours of approximately ~1–2 mm in diameter, NOX oxidases sense hypoxia and can help to mediate activation of the angiogenic switch while maintaining unregulated cell growth and evasion of cell death. As the tumour continues to grow, a complex tumour environment, including stromal cells, endothelial cells and tumour-associated macrophages (TAMs), secrete various metastatic agonists. NOX oxidases are responsive to the extracellular fluid surrounding the tumour environment and facilitate invasion and metastasis.