NADPH oxidase NOX4 is a glycolytic regulator through mROS-HIF1α axis in thyroid carcinomas

Abstract

The function of the NAD(P)H oxidases (NOXs) family member NOX4 is to generate reactive oxygen species (ROS), however, the molecular function of NOX4 has not been fully studied and waiting to be clarified. To elucidate the function of endogenous Nox4 in human thyroid carcinomas, papillomatosis thyroid cancer cells were used to study the cell growth by knocking down the expression of NOX4 and knocking out its functional partner p22phox/CYBA. As a result, the increasement of mitochondrial ROS(mROS) was abolished due to both knockdown of NOX4 and p22phox knockout in hypoxia, which destabilized HIF1α decreasing glycolysis and retarded cell growth. These data suggests that Nox4 is potent oncotarget due to its role in regulating glycolysis through mROS-HIF1α pathway, thereby mediating proliferation in thyroid carcinomas.

Mechanistic Connections between Endoplasmic Reticulum (ER) Redox Control and Mitochondrial Metabolism

“…Together with Ero1α (see below), Nox4 is responsible for ROS output during ER stress [67]. While it is currently unclear whether Nox4 directly uses ROS to signal towards mitochondria, this enzyme-generated oxidative stress keeps glycolysis active via maintenance of Hif1α protein levels [68]. At the same time, high levels of Nox4 activity can coincide with repressed mitochondrial activity in a melanoma model, suggesting that calnexin could use Nox4-mediated ROS production to generally repress mitochondria [69].…”

H2O2 Metabolism in Normal Thyroid Cells and in Thyroid Tumorigenesis: Focus on NADPH Oxidases

“…A clinically relevant link between NOX4-mediated ROS generation and PTC development is suggested by some GeoProfile datasets that show elevated NOX4 expression in PTC biopsies compared to biopsies obtained from the paired, non-affected thyroid (GDS1732/219773_at and GDS1732/236843_at). Taken together, these data point towards a possible role for NOX4 in PTC proliferation and imply NOX4 as a molecule of interest in pharmaceutical targeting of human thyroid cancers [27,135]. NOX4 is also related to another aspect of tumor propagation, namely in the interaction between the tumor and its microenvironment.…”

“…Another study highlighted a different role for NOX4 in thyroid carcinogenesis by demonstrating that NOX4-related ROS production is an essential component in the metabolic adaptation of PTC cells [135]. Malignant tumors are hypoxic due to a relatively lower capillarization rate compared to their unbridled proliferation [136].…”

“…NOX4 is a target of HIF-1α and is a critical player in the maintenance of hypoxia-related ROS production and proliferation [146]. In PTC cells NOX4 knockdown diminished proliferation, reduced mitochondrial ROS production and decreased HIF-1α stabilization [135]. In addition, NOX4 was essential for the metabolic switch towards anaerobic glycolysis, an important component in the maintenance of cell proliferation of tumorous cells [135].…”

“…In PTC cells NOX4 knockdown diminished proliferation, reduced mitochondrial ROS production and decreased HIF-1α stabilization [135]. In addition, NOX4 was essential for the metabolic switch towards anaerobic glycolysis, an important component in the maintenance of cell proliferation of tumorous cells [135]. Thyroid cancers were also described to contain more of the activated (phosphorylated) form of AMP Kinase (AMPK) [147,148].…”