Role of the NADPH Oxidases DUOX and NOX4 in Thyroid Oxidative Stress

Abstract

Somatic mutations are present at high levels in the rat thyroid gland, indicating that the thyrocyte is under oxidative stress, a state in which cellular oxidant levels are high. The most important class of free radicals, or reactive metabolites, is reactive oxygen species (ROS), such as superoxide anion (O₂^-), hydroxyl radical (OH) and hydrogen peroxide (H₂O₂). The main source of ROS in every cell type seems to be mitochondrial respiration; however, recent data support the idea that NADPH:O(₂) oxidoreductase flavoproteins or simply NADPH oxidases (NOX) are enzymes specialized in controlled ROS generation at the subcellular level. Several decades ago, high concentrations of H₂O₂ were detected at the apical surface of thyrocytes, where thyroid hormone biosynthesis takes place. Only in the last decade has the enzymatic source of H₂O₂ involved in thyroid hormone biosynthesis been well characterized. The cloning of two thyroid genes encoding NADPH oxidases dual oxidases 1 and 2 (DUOX1 and DUOX2) revealed that DUOX2 mutations lead to hereditary hypothyroidism in humans. Recent reports have also described the presence of NOX4 in the thyroid gland and have suggested a pathophysiological role of this member of the NOX family. In the present review, we describe the participation of NADPH oxidases not only in thyroid physiology but also in gland pathophysiology, particularly the involvement of these enzymes in the regulation of thyroid oxidative stress.

Mutant MYO1F alters the mitochondrial network and induces tumor proliferation in thyroid cancer

“…It has been reported that the establishment and maintenance of a transformed state is related to the presence of extracellular ROS, in particular, superoxide anion generated by a specific membrane‐associated NADPH‐oxidase, NOX1 . In fact, oncogenic activation of proliferative/mitogenic pathways has been associated with increased ROS production due to activation of the membrane‐bound NADPH oxidases . We did not detect differences among NOX1 protein levels, but this finding did not exclude an increased activation of this enzyme in the cells carrying the mutant MYO1F protein.…”

Endothelial cell tumor growth is Ape/ref-1 dependent

“…Elevated levels of Nox-4 have been previously reported for several other tumors including breast, thyroid, glioblastoma, and melanoma (8,35,51,59). The fact that EC tumors share a common pathological finding of elevated Nox-4 activity with other tumor types suggests that this source of ROS production and oxidative stress plays a fundamental role in malignant transformation.…”

Papillary Thyroid Carcinoma: A Malignant Tumor with Increased Antioxidant Defense Capacity

“…The main source of ROS in all cells appears to be mitochondrial respiration, though recent data reveal that NADPH oxidases (NOX) allow controlled ROS generation at the subcellular level (Fortunato et al 2014). Several decades ago, high concentrations of hydrogen peroxide were detected on the thyrocyte apical surface, where thyroid hormone biosynthesis takes place, and later the enzymatic source of hydrogen peroxide involved in thyroid hormone biosynthesis was characterized by cloning of genes encoding NADPH oxidases: dual oxidases 1 and 2 (DUOX1 and DUOX2) (Carvalho and Dupuy 2013). Besides its physiological role, oxidative stress appears to accompany thyroid carcinogenesis and to influence disease progression (Young et al 2010;Stanley et al 2016;Ece et al 2013;Yanagawa et al 1999).…”