Cellular and exosomal GPx1 are essential for controlling hydrogen peroxide balance and alleviating oxidative stress in hypoxic glioblastoma
Fu-Ju Lei,
Jung-Ying Chiang,
Huan-Jui Chang,
Der-Cherng Chen,
Hwai-Lee Wang,
Hsi-An Yang,
Kai-Yu Wei,
Yen‐Chih Huang,
Chi-Chung Wang,
Sung-Tai Wei,
Chia-Hung Hsieh
Affiliations
Fu-Ju Lei
Graduate Institute of Clinical Medical Sciences, China Medical University, Taichung, Taiwan
Jung-Ying Chiang
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Department of Neurosurgery, China Medical University Hsinchu Hospital, Hsinchu, Taiwan
Huan-Jui Chang
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
Der-Cherng Chen
Department of Neurosurgery, China Medical University and Hospital, Taichung, Taiwan
Hwai-Lee Wang
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
Hsi-An Yang
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
Kai-Yu Wei
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Mingdao High School, Taichung, Taiwan
Yen‐Chih Huang
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Department of Medical Imaging, China Medical University and Hospital, Taichung, Taiwan
Chi-Chung Wang
Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei, Taiwan
Sung-Tai Wei
Division of Neurosurgery, Department of Surgery, An Nan Hospital, China Medical University, Tainan, Taiwan
Chia-Hung Hsieh
Graduate Institute of Clinical Medical Sciences, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; Corresponding author. No. 91, Hsueh-Shih Road, Taichung, 404, Taiwan.
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.
