Cellular and exosomal GPx1 are essential for controlling hydrogen peroxide balance and alleviating oxidative stress in hypoxic glioblastoma

Tumor hypoxia promotes malignant progression and therapeutic resistance in glioblastoma partly by increasing the production of hydrogen peroxide (H(2)O(2)), a type of reactive oxygen species critical for cell metabolic responses due to its additional role as a second messenger. However, the catabolic pathways that prevent H(2)O(2) overload and subsequent tumor cell damage in hypoxic glioblastoma remain unclear. Herein, we present a hypoxia-coordinated H(2)O(2) regulatory mechanism whereby excess H(2)O(2) in glioblastoma induced by hypoxia is diminished by glutathione peroxidase 1 (GPx1), an antioxidant enzyme detoxifying H(2)O(2), via the binding of hypoxia-inducible factor-1α (HIF-1α) to GPx1 promoter. Depletion of GPx1 results in H(2)O(2) overload and apoptosis in glioblastoma cells, as well as growth inhibition in glioblastoma xenografts. Moreover, tumor hypoxia increases exosomal GPx1 expression, which assists glioblastoma and endothelial cells in countering H(2)O(2) or radiation-induced apoptosis in vitro and in vivo. Clinical data explorations further demonstrate that GPx1 expression was positively correlated with tumor grade and expression of HIF-1α, HIF-1α target genes, and exosomal marker genes; by contrast, it was inversely correlated with the overall survival outcome in human glioblastoma specimens. Our analyses validate that the redox balance of H(2)O(2) within hypoxic glioblastoma is clinically relevant and could be maintained by HIF-1α-promoted or exosome-related GPx1.