NADPH Oxidase Subunit 4-Mediated Reactive Oxygen Species Contribute to Cycling Hypoxia-Promoted Tumor Progression in Glioblastoma Multiforme

Hsieh, Chi-Hsun; Shyu, Woei Cherng; Chiang, Chien Yi; Kuo, Jung Wen; Shen, Wu‐Chung; Liu, Ru‐Shi

doi:10.1371/journal.pone.0023945

Cited by 92 publications

(96 citation statements)

References 39 publications

(62 reference statements)

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“…This response can be elicited by hypoxia itself; however, there is increasing evidence that ROS are able to potentiate the response. Increased ROS level and increased NOX4 expression have been observed in glioblastoma cell lines under hypoxic condition, and it has been suggested that NOX4-generated ROS promote the activation of HIF-1 and of glioblastoma progression (73).…”

Section: Nox In Cns Tumorsmentioning

confidence: 99%

New Insights onNOXEnzymes in the Central Nervous System

Nayernia

Jaquet

Krause

2014

Antioxidants & Redox Signaling

238

222

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Significance: There is increasing evidence that the generation of reactive oxygen species (ROS) in the central nervous system (CNS) involves the NOX family of nicotinamide adenine dinucleotide phosphate oxidases. Controlled ROS generation appears necessary for optimal functioning of the CNS through fine-tuning of redoxsensitive signaling pathways, while overshooting ROS generation will lead to oxidative stress and CNS disease. Recent Advances: NOX enzymes are not only restricted to microglia (i.e. brain phagocytes) but also expressed in neurons, astrocytes, and the neurovascular system. NOX enzymes are involved in CNS development, neural stem cell biology, and the function of mature neurons. While NOX2 appears to be a major source of pathological oxidative stress in the CNS, other NOX isoforms might also be of importance, for example, NOX4 in stroke. Globally speaking, there is now convincing evidence for a role of NOX enzymes in various neurodegenerative diseases, cerebrovascular diseases, and psychosis-related disorders. Critical Issues: The relative importance of specific ROS sources (e.g., NOX enzymes vs. mitochondria; NOX2 vs. NOX4) in different pathological processes needs further investigation. The absence of specific inhibitors limits the possibility to investigate specific therapeutic strategies. The uncritical use of non-specific inhibitors (e.g., apocynin, diphenylene iodonium) and poorly validated antibodies may lead to misleading conclusions. Future Directions: Physiological and pathophysiological studies with cell-type-specific knock-out mice will be necessary to delineate the precise functions of NOX enzymes and their implications in pathomechanisms. The development of CNS-permeant, specific NOX inhibitors will be necessary to advance toward therapeutic applications. Antioxid. Redox Signal. 20, 2815Signal. 20, -2837

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Section: Nox In Cns Tumorsmentioning

confidence: 99%

New Insights onNOXEnzymes in the Central Nervous System

Nayernia

Jaquet

Krause

2014

Antioxidants & Redox Signaling

238

222

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“…To mimic the clinical setting, we sought to test the efficacy of TAT-Lp15 when added to standard-of-care treatment with radiation plus temozolomide. BLI was utilized to assess intracranial tumor growth in the orthotopic GBM8401/SFFVLucGFP xenograft model (16,17,21). Consistent with the in vitro studies, mice that had TAT-Lp15 treatment before initiation of the combination of temozolomide and radiation treatment had significantly better tumor growth delay and survival rate than those pretreated with TAT-K22 or vehicle (Fig.…”

Section: Livin Blockage Enhances the Efficiency Of Radiation Plus Temmentioning

confidence: 60%

“…Here, we first demonstrate that the tumor microenvironment mediated expression pattern of Livin. To directly distinguish and isolate hypoxic tumor subpopulations from solid tumors, we used a reliable protocol of cycling-and chronic-hypoxic cell identification derived from our previous studies that allows subsequent immunofluorescence imaging and flow-cytometric analysis of the biosignature of these cells (16). Our results indicate that both of probable cycling and chronic hypoxic areas are important in tumor microenvironment-mediated Livin induction.…”

Section: Discussionmentioning

confidence: 94%

“…S1 and S2). To better verify endogenous tumor hypoxia-mediated Livin expression in the solid tumor, Hoechst 33342 staining and HIF1 activation labeling together with immunofluorescence imaging and FACS were utilized to isolate hypoxic tumor subpopulations from human glioblastoma xenografts as described in our previous studies (16)(17)(18). The GBM8401/hif-1-r tumors showed highly heterogeneous Hoechst 33342 staining and HIF1 activation on immunofluorescence images ( Fig.…”

Section: Tumor Hypoxia Induces Livin Expressionmentioning

confidence: 99%

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Livin Contributes to Tumor Hypoxia–Induced Resistance to Cytotoxic Therapies in Glioblastoma Multiforme

Hsieh

Lin

et al. 2015

Clinical Cancer Research

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Purpose: Tumor hypoxia is one of the crucial microenvironments to promote therapy resistance (TR) in glioblastoma multiforme (GBM). Livin, a member of the family of inhibitor of apoptosis proteins, contributes antiapoptosis. However, the role of tumor hypoxia in Livin regulation and its impact on TR are unclear.Experimental Design: Livin expression and apoptosis for tumor hypoxic cells derived from human glioblastoma xenografts or in vitro hypoxic stress-treated glioblastoma cells were determined by Western blotting, immunofluorescence imaging, and annexin V staining assay. The mechanism of hypoxia-induced Livin induction was investigated by chromatin immunoprecipitation assay and reporter assay. Genetic and pharmacologic manipulation of Livin was utilized to investigate the role of Livin on tumor hypoxia-induced TR in vitro or in vivo.Results: The upregulation of Livin expression and downregulation of caspase activity were observed under cycling and chronic hypoxia in glioblastoma cells and xenografts, concomitant with increased TR to ionizing radiation and temozolomide. However, knockdown of Livin inhibited these effects. Moreover, hypoxia activated Livin transcription through the binding of hypoxiainducible factor-1a to the Livin promoter. The targeted inhibition of Livin by the cell-permeable peptide (TAT-Lp15) in intracerebral glioblastoma-bearing mice demonstrated a synergistic suppression of tumor growth and increased the survival rate in standardof-care treatment with radiation plus temozolomide.Conclusions: These findings indicate a novel pathway that links upregulation of Livin to tumor hypoxia-induced TR in GBM and suggest that targeting Livin using cell-permeable peptide may be an effective therapeutic strategy for tumor microenvironmentinduced TR.

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“…Nox4 is known as a dominant isoform of Nox family in glioblastoma tissues and cell lines, and its expression is increased under hypoxic stress [19,24,25]. Semi-quantitative RT-PCR analysis showed that Nox4 mRNA level was increased in hypoxia exposed U87 and U373 cells, while detectable change of Nox1, Nox2 and Nox5 mRNA was not observed under hypoxic stress (Fig.…”

Section: Nox4 Expression Is Increased In Hypoxic Glioblastomamentioning

confidence: 92%

Reactive oxygen species production has a critical role in hypoxia-induced Stat3 activation and angiogenesis in human glioblastoma

Yu¹,

Park

et al. 2015

J Neurooncol

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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.

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NADPH Oxidase Subunit 4-Mediated Reactive Oxygen Species Contribute to Cycling Hypoxia-Promoted Tumor Progression in Glioblastoma Multiforme

Cited by 92 publications

References 39 publications

New Insights onNOXEnzymes in the Central Nervous System

New Insights onNOXEnzymes in the Central Nervous System

Livin Contributes to Tumor Hypoxia–Induced Resistance to Cytotoxic Therapies in Glioblastoma Multiforme

Reactive oxygen species production has a critical role in hypoxia-induced Stat3 activation and angiogenesis in human glioblastoma

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