title: Reactive oxygen species production has a critical role in hypoxia-induced Stat3 activation and angiogenesis in human glioblastoma.
abstract: Glioblastoma is the most aggressive primary brain tumor with hypoxia-associated morphologic features including pseudopalisading necrosis and endothelial hyperplasia. It has been known that hypoxia can activate signal transducer and activator of transcription 3 (Stat3) and subsequently induce angiogenesis. However, the molecular mechanism underlying hypoxia-induced Stat3 activation has not been defined. In this study, we explored the possible implication of reactive oxygen species (ROS) in hypoxia-driven Stat3 activation in human glioblastoma. We found that hypoxic stress increased ROS production as well as Stat3 activation and that ROS inhibitors (diphenyleneiodonium, rotenone and myxothiazol) and an antioxidant (N-acetyl-L-cysteine) blocked Stat3 activation under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is involved in hypoxia-induced ROS production. Nox4 expression was found to be increased at both mRNA and protein levels in hypoxic glioblastoma cells. In addition, siRNA-mediated knockdown of Nox4 expression abolished hypoxia induced Stat3 activation and vascular endothelial growth factor expression, which is associated with tumor cells' ability to trigger tube formation of endothelial cells in vitro. Our findings indicate that elevated ROS production plays a crucial role for Stat3 activation and angiogenesis in hypoxic glioblastoma cells.
authors: Department of Neurosurgery, College of Medicine, Korea University, #126, 5-ga, Anam-Dong, Seongbuk-Gu, Seoul, 136-705, Korea.|School of Life Sciences and Biotechnology, Korea University, 5-1 Anam-Dong, Seongbuk-Gu, Seoul, 136-701, Korea.
authors: Mi Ok
authors: MO
authors: Yu
authors: Department of Neurosurgery, College of Medicine, Korea University, #126, 5-ga, Anam-Dong, Seongbuk-Gu, Seoul, 136-705, Korea.
authors: Kyung-Jae
authors: KJ
authors: Park
authors: Department of Neurosurgery, College of Medicine, Korea University, #126, 5-ga, Anam-Dong, Seongbuk-Gu, Seoul, 136-705, Korea.
authors: Dong-Hyuk
authors: DH
authors: Park
authors: Department of Neurosurgery, College of Medicine, Korea University, #126, 5-ga, Anam-Dong, Seongbuk-Gu, Seoul, 136-705, Korea.
authors: Yong-Gu
authors: YG
authors: Chung
authors: School of Life Sciences and Biotechnology, Korea University, 5-1 Anam-Dong, Seongbuk-Gu, Seoul, 136-701, Korea. chi6302@korea.ac.kr.
authors: Sung-Gil
authors: SG
authors: Chi
authors: Department of Neurosurgery, College of Medicine, Korea University, #126, 5-ga, Anam-Dong, Seongbuk-Gu, Seoul, 136-705, Korea. hermes23@kumc.or.kr.
authors: Shin-Hyuk
authors: SH
authors: Kang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D001932:Brain Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D042461:Vascular Endothelial Growth Factor A; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D000111:Acetylcysteine
keywords: Angiogenesis; Hypoxia; NADPH oxidase 4; Reactive oxygen species; Signal transducer and activator of transcription 3