NADPH oxidase‐derived reactive oxygen species: Dosis facit venenum

Schröder, Katrin

doi:10.1113/ep087125

Cited by 39 publications

(38 citation statements)

References 40 publications

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“…Oxidative stress caused by reactive oxygen species, a group of oxygen-based reactive molecules produced by ATO activated the NADPH-oxidase system, resulting in the disruption of mitochondrial membrane potential and subsequent apoptosis [27][28][29]. As published previously, the mRNA expression of NCF2/P67PHOX and GPPHOX91 were substantially higher in the presence of TG2 compared to NB4 TG2-KD and TG2-KO cells.…”

Section: Discussionsupporting

confidence: 55%

Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2

Jambrovics

Uray

Keillor

et al. 2020

Cancers

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Randomized trials in acute promyelocytic leukemia patients have shown that treatment with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is superior in efficacy to monotherapy, with significantly decreased mortality. So far, there are little data available to explain the success of the ATRA and ATO combination treatment in molecular terms. We showed that ATRA-and ATO-treated cells had the same capacity for superoxide production, which was reduced by two-thirds in the combined treatment. Secreted inflammatory biomarkers (monocyte chemoattractant protein-1 [MCP-1], interleukin-1 beta [IL-1β] and tumor necrosis factor-α [TNF-α]) were significantly decreased and were further reduced in a transglutaminase 2 (TG2) expression-dependent manner. The amount of secreted TNF-α in the supernatant of NB4 TG2 knockout cells was close to 50 times lower than in ATRA-treated differentiated wild-type NB4 cells. The irreversible inhibitor of TG2 NC9 not only decreased reactive oxygen species production 28-fold, but decreased the concentration of MCP-1, IL-1β and TNF-α 8-, 15-and 61-fold, respectively in the combined ATRA + ATO-treated wild-type NB4 cell culture. We propose that atypical expression of TG2 leads to the generation of inflammation, which thereby serves as a potential target for the prevention of differentiation syndrome.(ATRA) both activates the PML-RARα chimera protein and initiates its proteolysis, resulting in the differentiation of APL leukemic cells [1][2][3].In the 2000s, arsenic trioxide (As 2 O 3 /ATO) was approved by the Food and Drug Administration (US FDA) to treat APL. Clinical data have shown that ATO, either as a single agent or combined with ATRA, can improve the outcomes in newly diagnosed and relapsed APL, compared to ATRA treatment alone [4][5][6].When combined with ATRA and chemotherapy, ATO can induce complete remission of APL patients, with a five-year overall survival rate up to 90% [5]. At the molecular level, ATO exhibits cytotoxic effects in a concentration-dependent manner, while at lower concentrations (< 0.5 µM), ATO can induce partial differentiation and at higher concentrations (> 0.5 µM), it initiates apoptosis of APL cells. Some of the signal transduction pathways and transactivations of transcription factors involved are arsenic-induced and redox-sensitive. These include the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases 1/2 (ERK1/2), stress-activated protein kinase/Jun-N terminal protein kinases (SAPK/JNK), the apoptosis signal-regulating kinase 1/thioredoxin (ASK1/TRX) system, the AKT-mTOR pathway, transcription factor AP-1 and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [7]. Although both ATO and ATRA prime the PML-RARα oncoprotein for proteolysis, only ATO is effective as a monotherapy, through the elimination of residual leukemia-initiating cells. The major limitation to ATO treatment is coagulopathy, which is one of the major causes of early death in APL, driven by procoagulant and fibrino...

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Section: Discussionsupporting

confidence: 55%

Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2

Jambrovics

Uray

Keillor

et al. 2020

Cancers

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“…Most prominently Nox4 is localized in the endoplasmic reticulum and the perinuclear membrane system [ 13 ]. As HDAC4 shuttles between cytosol and nucleus, it is possible that HDAC4 passes an area similar to a micro domain with high H 2 O 2 concentration made by Nox4, a redox cloud [ 29 ]. In cardiac myocytes, oxidation of HDAC4 can be reversed by the reductase Trx1 and reduction of Cys667 and 669 in HDAC4 inhibits its nuclear export independently of its phosphorylation status [ 1 ].…”

Section: Discussionmentioning

confidence: 99%

Oxidation of HDAC4 by Nox4-derived H2O2 maintains tube formation by endothelial cells

et al. 2020

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NADPH oxidases produce reactive oxygen species that differ in localization, type and concentration. Within the Nox family only Nox4 produces H 2 O 2 which can directly oxidize cysteine residues. With this post-translational modification, activity, stability, localization and protein-protein interactions of the affected protein is altered. Nox4 controls differentiation, cellular homeostasis and prevents inflammation. Therefore, is likely that epigenetic mechanisms contribute to the effects of Nox4. One group of epigenetic modifiers are class IIa histone deacetylases (HDACs). We hypothesize that Nox4-derived H 2 O 2 oxidizes HDACs and analyzed whether HDACs can be differentially oxidized by Nox4. As an artificial system, we utilized HEK293 cells, overexpressing Nox4 in a tetracycline-inducible manner. HDAC4 was oxidized upon Nox4 overexpression. Additionally, Nox4 overexpression increased HDAC4 phosphorylation on Ser632. H 2 O 2 disrupted HDAC4/Mef2A complex, which de-represses Mef2A. In endothelial cells such as HUVECs and HMECs, overexpression of HDAC4 significantly reduced tube formation. Overexpression of a redox insensitive HDAC4 had no effect on endothelial tube formation. Treatment with H 2 O 2 , induction of Nox4 expression by treatment of the cells with TGFβ and co-overexpression of Nox4 not only induced phosphorylation of HDAC4, but also restored the repressive effect of HDAC4 for tube formation, while overexpression of a redox dead mutant of Nox4 did not. Taken together, Nox4 oxidizes HDAC4, increases its phosphorylation, and eventually ensures proper tube formation by endothelial cells.

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“…These results are in line with the changing view of ROS. They are no longer regarded as destructive correlates of oxidative stress only, but their importance in the regulation of cellular functions and in the maintenance of the essential redox homeostasis is being more and more recognized [5,6,7]. Yet, ROS in higher concentrations are indeed often associated with cell death [8,9,10].…”

Section: Introductionmentioning

confidence: 99%

A Role for H2O2 and TRPM2 in the Induction of Cell Death: Studies in KGN Cells

et al. 2019

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Recent studies showed that KGN cells, derived from a human granulosa cell tumor (GCT), express NADPH oxidase 4 (NOX4), an important source of H2O2. Transient receptor potential melastatin 2 (TRPM2) channel is a Ca2+ permeable cation channel that can be activated by H2O2 and plays an important role in cellular functions. It is also able to promote susceptibility to cell death. We studied expression and functionality of TRPM2 in KGN cells and examined GCT tissue microarrays (TMAs) to explore in vivo relevance. We employed live cell, calcium and mitochondrial imaging, viability assays, fluorescence activated cell sorting (FACS) analysis, Western blotting and immunohistochemistry. We confirmed that KGN cells produce H2O2 and found that they express functional TRPM2. H2O2 increased intracellular Ca2+ levels and N-(p-Amylcinnamoyl)anthranilic acid (ACA), a TRPM2 inhibitor, blocked this action. H2O2 caused mitochondrial fragmentation and apoptotic cell death, which could be attenuated by a scavenger (Trolox). Immunohistochemistry showed parallel expression of NOX4 and TRPM2 in all 73 tumor samples examined. The results suggest that GCTs can be endowed with a system that may convey susceptibility to cell death. If so, induction of oxidative stress may be beneficial in GCT therapy. Our results also imply a therapeutic potential for TRPM2 as a drug target in GCTs.

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NADPH oxidase‐derived reactive oxygen species: Dosis facit venenum

Cited by 39 publications

References 40 publications

Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2

Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2

Oxidation of HDAC4 by Nox4-derived H2O2 maintains tube formation by endothelial cells

A Role for H2O2 and TRPM2 in the Induction of Cell Death: Studies in KGN Cells

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