AUTHOR=Jiang Hongxiang , Li Fei , Cai Linzhi , Chen Qianxue 

TITLE=Role of the TSPO–NOX4 axis in angiogenesis in glioblastoma

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.1001588

DOI=10.3389/fphar.2022.1001588

ISSN=1663-9812

ABSTRACT=<p><bold>Objective:</bold> Angiogenesis is a pathological feature of glioblastoma. Nicotinamide adenine dinucleotide phosphate oxidase 4 (<italic>NOX4</italic>) is a vital source of reactive oxygen species (ROS) related to angiogenesis. However, signaling pathways correlated with the isoform oxidase are unknown. The aim of this study was to elucidate the detailed mechanism of the role of <italic>NOX4</italic> in angiogenesis in glioblastoma.</p><p><bold>Methods:</bold> Public datasets were searched for studies on immunohistochemistry and western blotting to evaluate <italic>NOX4</italic> expression in glioma. The location of <italic>NOX4</italic> expression was detected by immunofluorescence. We conducted conditional deletion of the translocator protein (TSPO) targeting the protein with the synthetic ligand XBD173 in the glioblastoma mouse model. <italic>NOX4</italic> downregulation was conducted with the NOX4 inhibitor GLX351322, and ROS production and angiogenesis were detected in glioma tissues.</p><p><bold>Results:</bold> Clinical samples and public datasets showed that <italic>NOX4</italic> was upregulated and associated with the prognosis. <italic>NOX4</italic> is mainly expressed in endothelial cells of glioblastoma. Both TSPO and NOX4 promoted angiogenesis in an ROS-dependent manner, suggesting that TSPO triggered ROS production in glioblastoma <italic>via</italic> NOX4.</p><p><bold>Conclusion:</bold> These results showed that TSPO is an upstream target of NOX4-derived mitochondrial ROS, which is indispensable for NOX4-derived mitochondrial ROS-induced angiogenesis in glioblastoma. TSPO–NOX4 signaling could serve as a molecular target for therapeutic strategies for glioblastoma.</p>