PDF(Pubmed)
Abstract：
Tumor hypoxia promotes malignant progression and therapeutic resistance in glioblastoma partly by increasing the production of hydrogen peroxide (H2O2), 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 H2O2 overload and subsequent tumor cell damage in hypoxic glioblastoma remain unclear. Herein, we present a hypoxia-coordinated H2O2 regulatory mechanism whereby excess H2O2 in glioblastoma induced by hypoxia is diminished by glutathione peroxidase 1 (GPx1), an antioxidant enzyme detoxifying H2O2, via the binding of hypoxia-inducible factor-1α (HIF-1α) to GPx1 promoter. Depletion of GPx1 results in H2O2 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 H2O2 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 H2O2 within hypoxic glioblastoma is clinically relevant and could be maintained by HIF-1α-promoted or exosome-related GPx1.
摘要：
肿瘤缺氧部分通过增加过氧化氢（H2O2）的产生促进胶质母细胞瘤的恶性进展和治疗抗性，一种对细胞代谢反应至关重要的活性氧，由于其作为第二信使的额外作用。然而,在低氧性胶质母细胞瘤中防止H2O2超负荷和随后的肿瘤细胞损伤的分解代谢途径仍不清楚.在这里，我们提出了一种缺氧协调的H2O2调节机制，通过谷胱甘肽过氧化物酶1（GPx1）减少缺氧诱导的胶质母细胞瘤中过量的H2O2，一种抗氧化酶，通过将缺氧诱导因子-1α（HIF-1α）与GPx1启动子结合来解毒H2O2。GPx1的耗尽导致胶质母细胞瘤细胞中H2O2过载和凋亡，以及胶质母细胞瘤异种移植物的生长抑制。此外，肿瘤缺氧增加外泌体GPx1表达，这有助于胶质母细胞瘤和内皮细胞在体外和体内对抗H2O2或辐射诱导的细胞凋亡。临床数据探索进一步表明GPx1的表达与肿瘤分级和HIF-1α的表达呈正相关。HIF-1α靶基因,和外泌体标记基因；相比之下，它与人类胶质母细胞瘤标本的总体生存结局呈负相关.我们的分析证实，缺氧胶质母细胞瘤中H2O2的氧化还原平衡是临床相关的，并且可以通过HIF-1α促进或外泌体相关的GPx1维持。
