NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways

Abid, M. Ruhul; Spokes, Katherine; Shih, Shou‐Ching; Aird, William C.

doi:10.1074/jbc.m702175200

Cited by 136 publications

(133 citation statements)

References 77 publications

(58 reference statements)

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“…However, several lines of evidence suggest an important role for NOX in tumor angiogenesis; for example, ROS generation through NOX4 contributes to induction of angiogenesis through upregulation of VEGF and hypoxia-inducible factor-1a in ovarian cancer cells (23,24). Abid and colleagues (25) found that NOX activity is required for VEGF receptormediated cell signaling. This discrepancy may be due to the cell type-and/or isoform-specific action of NOX.…”

Section: Discussionmentioning

confidence: 99%

ALKBH3 Contributes to Survival and Angiogenesis of Human Urothelial Carcinoma Cells through NADPH Oxidase and Tweak/Fn14/VEGF Signals

Shimada

Fujii

Tsujikawa

et al. 2012

Clinical Cancer Research

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Purpose: The role and function of a novel human AlkB homologue, ALKBH3, in human urothelial carcinoma development were examined.Experimental design: Biologic roles of ALKBH3 were examined by gene silencing analysis using in vitro and in vivo siRNA transfection. Immunohistochemical analyses of ALKBH3 and the related molecules using human bladder cancer samples were conducted to estimate the association with clinicopathologic or prognostic parameters.Results: ALKBH3 knockdown induced cell cycle arrest at the G1 phase through downregulation of NAD(P)H oxidase-2 (NOX-2)-mediated generation of reactive oxygen species (ROS). ALKBH3 knockdown reduced VEGF expression by reducing expression of tumor necrosis factor-like weak inducer of apoptosis (Tweak) and its receptor, fibroblast growth factor-inducible 14 (Fn14). Silencing of ALKBH3 or Tweak significantly suppressed invasion and angiogenesis of urothelial carcinoma in vivo as assessed both by a chorioallantoic membrane assay and in an orthotopic mouse model. Interestingly, not only urothelial carcinoma cells but also vascular endothelial cells within cancer foci expressed Fn14, which was strongly reduced by ALKBH3 and Tweak knockdown in vivo, suggesting that ALKBH3-dependent expression of Tweak stabilizes Fn14. Immunohistochemical examination showed high expression of ALKBH3, Tweak, and Fn14 in urothelial carcinoma, especially in high-grade, superficially, and deeply invasive carcinomas; moreover, Fn14-positive vessel counts within cancer foci were increased in invasive phenotypes.Conclusions: ALKBH3 contributes to development of urothelial carcinomas by accelerating their survival, angiogenesis, and invasion through NOX-2-ROS and Tweak/Fn14-VEGF signals.

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Section: Discussionmentioning

confidence: 99%

ALKBH3 Contributes to Survival and Angiogenesis of Human Urothelial Carcinoma Cells through NADPH Oxidase and Tweak/Fn14/VEGF Signals

Shimada

Fujii

Tsujikawa

et al. 2012

Clinical Cancer Research

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“…Therefore, we believe that the inhibitory effect of atorvastatin on the activation of p38MAPK might be related to its antioxidant function. It has been reported that ROS increase the phosphorylation of a tyrosine or/and serine of MAPK [20] , while siRNAs against NADPH oxidases [36] suppress the phosphorylation of p38MAPK. Endogenous Nox4 [37] has been located to the nucleus of endothelial cells, which pointed to the nucleus as an intracellular site of ROS production.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin inhibits homocysteine-induced dysfunction and apoptosis in endothelial progenitor cells

Bao

2010

Acta Pharmacol Sin

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Aim: To investigate the protective effects of atorvastatin on homocysteine (Hcy)-induced dysfunction and apoptosis in endothelial progenitor cells (EPCs) and the possible molecular mechanisms. Methods: EPCs were divided into six groups: Hcy treatment groups (0, 50, and 500 μmol/L) and atorvastatin pretreatment groups (0.1, 1, and 10 μmol/L). EPC proliferation, migration, in vitro vasculogenesis activity, and apoptosis rate were assayed by the MTT assay, modified Boyden chamber assay, in vitro vasculogenesis kit, and AnnexinV-FITC apoptosis detection kit, respectively. The level of reactive oxygen species (ROS) in cells was measured using H 2 DCF-DA as a fluorescence probe. The activity of NADPH oxidase was evaluated with lucigenin-enhanced chemiluminescence. NO in the supernatant was detected by the nitrate reductase assay. The eNOS mRNA expression and p-eNOS, p-Akt, p-p38MAPK protein expression were measured by RT-PCR and Western blotting analysis, respectively. Caspase-3 activity was determined by colorimetric assay. Results: Hcy does-dependently impaired the proliferation, migration and in vitro vasculogenesis capacity of EPCs, induced cell apoptosis, increased ROS accumulation and NADPH oxidase activation, and decreased the secretion of NO compared with the control group (P<0.05 or P<0.01). The detrimental effects of Hcy were attenuated by atorvastatin pretreatment. Furthermore, Hcy caused a significant downregulation of eNOS mRNA, p-eNOS, and p-Akt protein expression as well as an upregulation of p-p38MAPK protein expression and caspase-3 activity. These effects of Hcy on EPCs were reversed by atorvastatin in a does-dependent manner. Conclusion: Atorvastatin inhibited homocysteine-induced dysfunction and apoptosis in endothelial progenitor cells, which may be related to its effects on suppressing oxidative stress, up-regulating Akt/eNOS and down-regulating the p38MAPK/caspase-3 signaling pathway.

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“…NADPH oxidase activity was measured as described previously [20]. Briefly, ESCs at certain differentiation days were collected and homogenized in buffer containing 20 mM KH 2 PO 4 (pH 7.0), 13 protease mixture inhibitor, 1 mM EGTA, 10 lg/ ml aprotinin, 0.7 lg/ml pepstatin, 0.5 lg/ml leupeptin, and 0.5 mM phenylmethylsulfonyl fluoride.…”

Section: Nadph Oxidase Activity Assaymentioning

confidence: 99%

CD38 Is Required for Neural Differentiation of Mouse Embryonic Stem Cells by Modulating Reactive Oxygen Species

et al. 2015

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CD38 is a multifunctional membrane enzyme and the main mammalian ADP-ribosyl cyclase, which catalyzes the synthesis and hydrolysis of cADPR, a potent endogenous Ca 21 mobilizing messenger. Here, we explored the role of CD38 in the neural differentiation of mouse embryonic stem cells (ESCs). We found that the expression of CD38 was decreased during the differentiation of mouse ESCs initiated by adherent monoculture. Perturbing the CD38/cADPR signaling by either CD38 knockdown or treatment of cADPR antagonists inhibited the neural commitment of mouse ESCs, whereas overexpression of CD38 promoted it. Moreover, CD38 knockdown dampened reactive oxygen species (ROS) production during neural differentiation of ESCs by inhibiting NADPH oxidase activity, while CD38 overexpression enhanced it. Similarly, application of hydrogen peroxide mitigated the inhibitory effects of CD38 knockdown on neural differentiation of ESCs. Taken together, our data indicate that the CD38 signaling pathway is required for neural differentiation of mouse ESCs by modulating ROS production. STEM CELLS 2015; 33:2664-2673 SIGNIFICANCE STATEMENTThe in vitro generation of neural lineage cells from embryonic stem (ES) cells is a promising approach to produce cells suitable for neural tissue repair and cell-based replacement therapies of the nervous system. The functions regulated by the CD38 signaling are diverse. Here we found that the CD38 signaling pathway is required for neural differentiation of mouse ES cells by modulating ROS production. Our findings not only increase our understanding of ES cell differentiation and embryonic neural development, but also encourage the application of therapies based on ES cells in the treatment of neurological and psychiatric diseases.

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NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways

Cited by 136 publications

References 77 publications

ALKBH3 Contributes to Survival and Angiogenesis of Human Urothelial Carcinoma Cells through NADPH Oxidase and Tweak/Fn14/VEGF Signals

ALKBH3 Contributes to Survival and Angiogenesis of Human Urothelial Carcinoma Cells through NADPH Oxidase and Tweak/Fn14/VEGF Signals

Atorvastatin inhibits homocysteine-induced dysfunction and apoptosis in endothelial progenitor cells

CD38 Is Required for Neural Differentiation of Mouse Embryonic Stem Cells by Modulating Reactive Oxygen Species

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